Anti-B7-H1 and Anti-CTLA-4 Antibodies for Treating Non-Small Cell Lung Cancer

ABSTRACT

Provided herein are methods of treating non-small cell lung cancers comprising administering an effective amount of MEDI4736 or an antigen-binding fragment thereof and tremelimumab or an antigen-binding fragment thereof.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.16/256,022, filed Jan. 24, 2019, which is a continuation of U.S. patentapplication Ser. No. 14/710,101, filed May 12, 2015, now U.S. Pat. No.10,232,040, which claims priority to and the benefit of U.S. ProvisionalPatent Application Ser. No. 61/992,658, filed May 13, 2014, U.S.Provisional Patent Application Ser. No. 62/105,992, filed Jan. 21, 2015,and U.S. Provisional Patent Application Ser. No. 62/114,336, filed Feb.10, 2015. The entire contents of each of these applications are herebyincorporated by reference herein.

SEQUENCE LISTING

A computer readable form of the Sequence Listing is filed with thisapplication by electronic submission and is incorporated into thisapplication by reference in its entirety. The sequence listing submittedherewith is contained in the file created Aug. 3, 2022, entitled“20-1563-US-CON2_SequenceListing.xml” and is 21.3 kilobytes in size.

BACKGROUND

Cancer continues to be a major global health burden. Despite progress inthe treatment of cancer, there continues to be an unmet medical need formore effective and less toxic therapies, especially for those patientswith advanced disease or cancers that are resistant to existingtherapeutics.

The role of the immune system, in particular T cell-mediatedcytotoxicity, in tumor control is well recognized. There is mountingevidence that T cells control tumor growth and survival in cancerpatients, both in early and late stages of the disease. However,tumor-specific T-cell responses are difficult to mount and sustain incancer patients.

Two T cell pathways receiving significant attention to date signalthrough cytotoxic T lymphocyte antigen-4 (CTLA-4, CD152) and programmeddeath ligand 1 (PD-L1, also known as B7-H1 or CD274).

CTLA4 is expressed on activated T cells and serves as a co-inhibitor tokeep T cell responses in check following CD28-mediated T cellactivation. CTLA4 is believed to regulate the amplitude of the earlyactivation of naïve and memory T cells following TCR engagement and tobe part of a central inhibitory pathway that affects both antitumorimmunity and autoimmunity. CTLA4 is expressed exclusively on T cells,and the expression of its ligands CD80 (B7.1) and CD86 (B7.2), islargely restricted to antigen-presenting cells, T cells, and otherimmune mediating cells. Antagonistic anti-CTLA4 antibodies that blockthe CTLA4 signaling pathway have been reported to enhance T cellactivation. One such antibody, ipilimumab, was approved by the FDA in2011 for the treatment of metastatic melanoma. Another anti-CTLA4antibody, tremelimumab, was tested in phase III trials for the treatmentof advanced melanoma, but did not significantly increase the overallsurvival of patients compared to the standard of care (temozolomide ordacarbazine) at that time.

PD-L1 is also part of a complex system of receptors and ligands that areinvolved in controlling T-cell activation. In normal tissue, PD-L1 isexpressed on T cells, B cells, dendritic cells, macrophages, mesenchymalstem cells, bone marrow-derived mast cells, as well as variousnonhematopoietic cells. Its normal function is to regulate the balancebetween T-cell activation and tolerance through interaction with its tworeceptors: programmed death 1 (also known as PD-1 or CD279) and CD80(also known as B7-1 or B7.1). PD-L1 is also expressed by tumors and actsat multiple sites to help tumors evade detection and elimination by thehost immune system. PD-L1 is expressed in a broad range of cancers witha high frequency. In some cancers, expression of PD-L1 has beenassociated with reduced survival and unfavorable prognosis. Antibodiesthat block the interaction between B7-H1 and its receptors are able torelieve PD-L1-dependent immunosuppressive effects and enhance thecytotoxic activity of antitumor T cells in vitro. MEDI4736 is a humanmonoclonal antibody directed against human PD-L1 that is capable ofblocking the binding of PD-L1 to both the PD-1 and CD80 receptors.

Despite the significant progress made over the past decade in developingstrategies for combatting cancer and other diseases, patients withadvanced, refractory and metastatic disease have limited clinicaloptions. Chemotherapy, irradiation, and high dose chemotherapy havebecome dose limiting. There remains a substantial unmet need for newless-toxic methods and therapeutics that have better therapeuticefficacy, longer clinical benefit, and improved safety profiles,particularly for those patients with advanced disease or cancers thatare resistant to existing therapeutics.

BRIEF SUMMARY

The invention provides a method of treating non-small cell lung cancer(NSCLC) in a human patient, comprising administering 1 mg/kg of MEDI4736or an antigen-binding fragment thereof and 1 mg/kg tremelimumab or anantigen-binding fragment thereof to the patient.

The invention also provides a method of treating a NSCLC in a humanpatient, comprising administering 3 mg/kg of MEDI4736 or anantigen-binding fragment thereof and 1 mg/kg tremelimumab or anantigen-binding fragment thereof to the patient.

The invention also provides a method of treating NSCLC in a humanpatient, comprising administering 10 mg/kg of MEDI4736 or anantigen-binding fragment thereof and 1 mg/kg tremelimumab or anantigen-binding fragment thereof to the patient.

The invention also provides a method of treating NSCLC in a humanpatient, comprising administering 15 mg/kg of MEDI4736 or anantigen-binding fragment thereof and 1 mg/kg tremelimumab or anantigen-binding fragment thereof to the patient.

The invention also provides a method of treating NSCLC in a humanpatient, comprising administering 10 mg/kg of MEDI4736 or anantigen-binding fragment thereof and 3 mg/kg tremelimumab or anantigen-binding fragment thereof to the patient.

The invention also provides a method of treating NSCLC in a humanpatient, comprising administering 15 mg/kg of MEDI4736 or anantigen-binding fragment thereof and 3 mg/kg tremelimumab or anantigen-binding fragment thereof to the patient.

The invention also provides a method of treating NSCLC in a humanpatient, comprising administering 20 mg/kg of MEDI4736 or anantigen-binding fragment thereof and 1 mg/kg tremelimumab or anantigen-binding fragment thereof to the patient.

The invention also provides a method of treating NSCLC in a humanpatient, comprising administering 15 mg/kg of MEDI4736 or anantigen-binding fragment thereof and 10 mg/kg tremelimumab or anantigen-binding fragment thereof to the patient.

The invention also provides a method of treating NSCLC in a humanpatient, comprising administering 20 mg/kg of MEDI4736 or anantigen-binding fragment thereof and 3 mg/kg tremelimumab or anantigen-binding fragment thereof to the patient.

The invention also provides a method of treating NSCLC in a humanpatient, comprising administering 20 mg/kg of MEDI4736 or anantigen-binding fragment thereof and 10 mg/kg tremelimumab or anantigen-binding fragment thereof to the patient.

The invention also provides a method of treating NSCLC in a humanpatient, comprising administering 10 mg/kg of MEDI4736 or anantigen-binding fragment thereof and 10 mg/kg tremelimumab or anantigen-binding fragment thereof to the patient.

The invention also provides a method of treating NSCLC in a humanpatient, comprising administering 3 mg/kg of MEDI4736 or anantigen-binding fragment thereof and 3 mg/kg tremelimumab or anantigen-binding fragment thereof to the patient.

The invention also provides a method of treating NSCLC in a humanpatient, comprising administering 3 mg/kg of MEDI4736 or anantigen-binding fragment thereof and 10 mg/kg tremelimumab or anantigen-binding fragment thereof to the patient.

The invention also provides a method of treating NSCLC in a humanpatient, comprising administering 1 mg/kg of MEDI4736 or anantigen-binding fragment thereof and 3 mg/kg tremelimumab or anantigen-binding fragment thereof to the patient.

The invention also provides a method of treating NSCLC in a humanpatient, comprising administering 1 mg/kg of MEDI4736 or anantigen-binding fragment thereof and 10 mg/kg tremelimumab or anantigen-binding fragment thereof to the patient.

The invention also provides a method of treatment comprisingadministering MEDI4736 or an antigen-binding fragment thereof (e.g., at1 mg/kg, 3 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg), and tremelimumab oran antigen-binding fragment thereof (e.g., at 1 mg/kg, 3 mg/kg, 10mg/kg) to a patient identified as having a PD-L1⁻ or PD-L1⁺ NSCLC.

In particular embodiments of any of the previous methods, the MEDI4736is administered every 4 weeks. In one particular embodiment, theMEDI4736 is administered every 4 weeks for 49 weeks. In particularembodiments of any of the previous methods, the MEDI4736 is administeredevery 2 weeks. In another embodiment, a total of 13 doses of MEDI4736 isadministered.

In particular embodiments of the previous aspects, the tremelimumab isadministered every 4 weeks for the first 21 weeks. In other embodimentsof the previous aspects, the tremelimumab is administered every 12 weeksfrom weeks 25 to 49. In still other embodiments of the previous aspects,a total of 9 doses of tremelimumab is administered.

The invention also provides a method of treating NSCLC in a humanpatient, comprising administering 10 mg/kg of MEDI4736 or anantigen-binding fragment thereof and 1 mg/kg tremelimumab or anantigen-binding fragment thereof to the patient, where the MEDI4736 isadministered every 2 weeks.

The invention also provides a method of treating NSCLC in a humanpatient, comprising administering 10 mg/kg of MEDI4736 or anantigen-binding fragment thereof and 3 mg/kg tremelimumab or anantigen-binding fragment thereof to the patient, where the MEDI4736 isadministered every 2 weeks.

The invention also provides a method of treating NSCLC in a humanpatient, comprising administering 10 mg/kg of MEDI4736 or anantigen-binding fragment thereof and 10 mg/kg tremelimumab or anantigen-binding fragment thereof to the patient, wherein the MEDI4736 isadministered every 2 weeks.

In particular embodiments of the previous aspects, the tremelimumab isadministered every 4 weeks for the first 25 weeks. In other embodimentsof the previous aspects, the tremelimumab is administered every 12 weeksfrom weeks 25 to 49. In still other embodiments of the previous aspects,a total of 9 doses of tremelimumab is administered.

The invention also provides a method of treating NSCLC in a humanpatient comprising administering MEDI4736 or an antigen-binding fragmentthereof and tremelimumab or an antigen-binding fragment thereof to thepatient, wherein the administrations result in a tumor response.

In the method of the invention, the administrations result in anincreased tumor response as compared to the administration of either theMEDI4736 or an antigen-binding fragment thereof or the tremelimumab oran antigen-binding fragment thereof alone.

In some embodiments, the tumor response can be detected by week 2, 4, 6,8, or 10. In other embodiments, the tumor response can be detected byweek 33. In other embodiments, the tumor response can be detected byweek 50.

The invention also provides a method of treating NSCLC in a humanpatient comprising administering MEDI4736 or an antigen-binding fragmentthereof and tremelimumab or an antigen-binding fragment thereof to thepatient, wherein the administrations increase progression-free survival.In some embodiments, the administrations result in an increase inprogression-free survival as compared to the administration of eitherthe MEDI4736 or an antigen-binding fragment thereof or the tremelimumabor an antigen-binding fragment thereof alone.

The invention also provides a method of treating NSCLC in a humanpatient comprising administering MEDI4736 or an antigen-binding fragmentthereof and tremelimumab or an antigen-binding fragment thereof to thepatient, wherein the administrations increase overall survival. In someembodiments, the administrations result in an increase in overallsurvival as compared to the administration of either the MEDI4736 or anantigen-binding fragment thereof or the tremelimumab or anantigen-binding fragment thereof alone.

In some embodiments of the methods of the invention, the administrationsresult in a tumor response. In some embodiments, the administrationsresult in an increased tumor response as compared to the administrationof either the MEDI4736 or an antigen-binding fragment thereof or thetremelimumab or an antigen-binding fragment thereof alone. In someembodiments, the tumor response can be detected by week 8. In someembodiments, the tumor response can be detected by week 33.

In some embodiments of the methods of the invention, the administrationsincrease progression-free survival. In some embodiments, theadministrations result in an increase in progression-free survival ascompared to the administration of either the MEDI4736 or anantigen-binding fragment thereof or the tremelimumab or anantigen-binding fragment thereof alone.

In some embodiments of the methods of the invention, the administrationsincrease overall survival. In some embodiments, the administrationsresult in an increase in overall survival as compared to theadministration of either the MEDI4736 or an antigen-binding fragmentthereof or the tremelimumab or an antigen-binding fragment thereofalone.

In particular embodiments of any of the previous methods, the MEDI4736is administered every 4 weeks. In one particular embodiment, theMEDI4736 is administered every 4 weeks for 49 weeks. In anotherembodiment, a total of 13 doses of MEDI4736 is administered.

In particular embodiments of the previous aspects, the tremelimumab isadministered every 4 weeks for the first 21 weeks. In other embodimentsof the previous aspects, tremelimumab is administered every 12 weeksfrom weeks 25 to 49 or following the first 6 doses. In still otherembodiments of the previous aspects, a total of 9 doses of tremelimumabis administered.

In some embodiments of the method of the invention, the administrationof tremelimumab or an antigen-binding fragment thereof is administeredabout every 4 weeks for seven administrations and then every 12 weeks.

In some embodiments of the method of the invention, the administrationreduces soluble PD-L1. In some embodiments, soluble PD-L1 is reduced byat least about 65%, 80%, 90%, 95% or 99%.

In some embodiments of the methods of the invention, the tumor isrefractory to at least one chemotherapeutic agent. Such chemotherapeuticagents may include, but are not limited to Vemurafenib, Erlotinib,Afatinib, Cetuximab, Carboplatin, Bevacizumab, Erlotinib, Gefitinib, orPemetrexed.

In some embodiments of the methods of the invention, the patient has anEastern Cooperative Oncology Group (ECOG) performance status of 0-1.

In some embodiments of the methods of the invention, the patient isimmunotherapy-naïve prior to the administration of MEDI4736 orantigen-binding fragment thereof and tremelimumab or antigen-bindingfragment thereof.

In some embodiments of the methods of the invention, the patient hasreceived immunotherapy prior to the administration of MEDI4736 orantigen-binding fragment thereof and tremelimumab or antigen-bindingfragment thereof.

In some embodiments of the methods of the invention, the administrationof MEDI4736 or an antigen-binding fragment thereof is by intravenousinfusion.

In some embodiments of the methods of the invention, the administrationof tremelimumab or an antigen-binding fragment thereof is by intravenousinfusion.

In particular embodiments of the methods of the invention, theadministrations reduce tumor size by at least about 10%, 25%, 50%, 75%or 100% relative to baseline.

In particular embodiments of the methods of the invention, the humanpatient has locally advanced unresectable or metastatic NSCLC. Inparticular embodiments of the methods of the invention, the NSCLC issquamous or non-squamous. In other embodiments of the methods of theinvention, the NSCLC comprises a KRAS-mutation or an EGFR-mutation.

In some embodiments of the methods of the invention, the MEDI4736 or anantigen-binding fragment thereof is MEDI4736 and wherein thetremelimumab or an antigen-binding fragment thereof is tremelimumab.

In another aspect the invention provides for a method of treating cancerwith MEDI4736 or an antigen-binding fragment of MEDI4736 in combinationwith tremelimumab or an antigen-binding fragment of tremelimumab. Insome embodiments of the invention the cancer is selected from prostatecancer, breast cancer, triple negative breast cancer, colon cancer, lungcancer, NSCLC, head and neck cancer, melanoma, gastric cancer,pancreatic cancer, ovarian cancer, renal cell carcinoma, and hepaticcancer.

BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES

FIG. 1 shows the treatment schema. MTD=maximum tolerated dose.

FIG. 2 shows the dose escalation and dose expansion schemas.

FIG. 3 shows the dose escalation study design. DLT=dose limitingtoxicity.

FIG. 4 provides a graph and a table showing the pharmacokinetic (PK)profile of MEDI4736. Q4W=every 4 weeks. LLOQ=Lower limit ofQuantification. AUC=area under curve.

FIG. 5 provides a graph and a table showing the pharmacokinetic profileof tremelimumab.

FIG. 6 is a graph showing the absolute concentration of soluble PD-L1profiles (sPD-L1).

FIG. 7 is a graph showing the percent suppression of soluble PD-L1.

FIG. 8 is a graph showing the pharmacokinetic (PK) parameters ofMEDI4736 in individual patients.

FIG. 9 is a graph showing the pharmacokinetic (PK) parameters oftremelimumab in individual patients.

FIGS. 10A and 10B are tables showing MEDI4736 and tremelimumab dosemodification due to grade 1 or grade 2 toxicity (10A) and grade 3 orgrade 4 toxicity (10B).

FIG. 11 is a table showing Study criteria.

FIG. 12 shows study enrollment.

FIG. 13 shows related adverse events (AEs) for patients dosed.

FIG. 14 shows tumor size change from baseline in first four cohorts.

FIG. 15 shows MEDI4736 and tremelimumab doses and schedules studied.

FIG. 16 shows suppression of sPD-L1 in individual profiles receivingMEDI4736 and tremelimumab in combination.

FIG. 17 shows suppression of sPD-L1 in individual profiles receivingMEDI4736 and tremelimumab in combination grouped by cohort.

FIG. 18 shows an increase in CD4 Ki67+ and CD8 Ki67 proliferating cellsfrom baseline in subjects receiving MEDI4736 and tremelimumab comparedto increases in those receiving MEDI4736 alone. Increases in CD4 Ki67+and CD8 Ki67 proliferating cells from baseline correlated withincreasing tremelimumab dose.

FIG. 19 shows an increase in CD4 ICOS+ and CD4 HLADR+ cells frombaseline in subjects receiving MEDI4736 and tremelimumab compared toincreases in those receiving MEDI4736 alone. Increases in CD4 ICOS+ andCD4 HLADR+ cells from baseline correlated with increasing tremelimumabdose.

FIG. 20 shows an increase in CD4+T effector cells from baseline insubjects receiving MEDI4736 and tremelimumab compared to the increase inthose receiving MEDI4736 alone. The increases in CD4+T effector cellsfrom baseline correlated with increasing tremelimumab dose.

FIG. 21 shows an increase in Treg cells from baseline in subjectsreceiving MEDI4736 and tremelimumab compared to the increase in thosereceiving MEDI4736 alone. The increases in Treg cells from baselinecorrelated with increasing tremelimumab dose.

FIG. 22 is a table showing the clinical activity of MEDI4736 therapy incombination with tremelimumab compared to MEDI4736 monotherapy.

FIG. 23 are spider plots showing change in tumor size from baseline incohorts anchored by tremelimumab dose: 1 mg/kg (upper left panel); 10mg/kg (upper right panel); and 3 mg/kg (lower panel).

FIG. 24 is a graph showing time of onset of related Grade 3 adverseevents (AE) in combination cohorts anchored by tremelimumab dose: 1mg/kg; 10 mg/kg; and 3 mg/kg, compared to MEDI4736 monotherapy.

FIG. 25 are spider plots showing change in tumor size from baseline incohorts anchored by MEDI4736 dose: 10 mg/kg Q4W (upper left panel); 15mg/kg Q4W (upper right panel); 20 mg/kg Q4W (lower left panel); and 10mg/kg Q2W (lower right panel).

FIG. 26 is a graph showing time of onset of related Grade 3 adverseevents (AE) in combination cohorts anchored by MEDI4736 dose: 1 mg/kg;10 mg/kg; and 3 mg/kg, compared to MEDI4736 monotherapy.

FIG. 27 are spider plots showing change in tumor size from baseline inselected cohorts of NSCLC patients receiving MEDI4736 and tremelimumab(left panel) compared to those receiving MEDI4736 (10 mg/kg Q4W) alone(right panel).

FIG. 28 are graphs showing time of onset of related Grade 3 adverseevents (AE) in selected combination cohorts (left and right panels),compared to MEDI4736 monotherapy (left panel).

FIG. 29 are spider plots showing change in tumor size from baseline inall study cohorts of patients with NSCLC receiving MEDI4736 andtremelimumab.

FIG. 30 are spider plots showing change in tumor size from baseline inselected cohorts of patients with PD-L1 negative NSCLC receivingMEDI4736 and tremelimumab (left panel) compared to those receivingMEDI4736 (10 mg/kg; CP1108) alone (right panel).

FIG. 31 are spider plots showing change in tumor size from baseline inselected cohorts of patients with PD-L1 positive NSCLC receivingMEDI4736 and tremelimumab (left panel) compared to those receivingMEDI4736 (10 mg/kg; CP1108) alone (right panel).

FIG. 32 are spider plots anchored by tremelimumab dose: 1 mg/kg (leftpanel), 3 mg/kg (center panel), and 10 mg/kg (right panel) showingchange in tumor size from baseline in selected cohorts of patients withPD-L1 negative NSCLC receiving MEDI4736 and tremelimumab.

FIG. 33 are spider plots anchored by MEDI4736 dose: 10 mg/kg Q4W (upperleft panel), 15 mg/kg (upper right panel), and 20 mg/kg (lower leftpanel) showing change in tumor size from baseline in selected cohorts ofpatients with PD-L1 negative NSCLC receiving MEDI4736 and tremelimumab.

FIGS. 34A-34D are spider plots showing change in tumor size frombaseline in NSCLC patients receiving MEDI4736 and tremelimumab in FIG.29 , grouped according to NSCLC PD-L1 status: all NSCLC patients (34A);patients identified as having PD-L1⁻ NSCLC (34B); patients identified ashaving PD-L1⁺ NSCLC (34C); and patients with NSCLC PD-L1 status notavailable (34D).

FIG. 35 is a waterfall plot showing best change in tumor size frombaseline in NSCLC patients receiving MEDI4736 and tremelimumab.

FIG. 36 is a waterfall plot showing best change in tumor size frombaseline in NSCLC patients receiving MEDI4736 and tremelimumab in FIG.35 , identified according to PD-L1 status of the NSCLC.

FIG. 37 is a swimlane plot showing duration of follow-up in NSCLCpatients receiving MEDI4736 and tremelimumab.

DETAILED DESCRIPTION

It is to be noted that the term “a” or “an” entity refers to one or moreof that entity; for example, “an antibody” is understood to representone or more antibodies. As such, the terms “a” (or “an”), “one or more,”and “at least one” can be used interchangeably herein.

Provided herein are methods for treating non-small cell lung cancer(NSCLC) using MEDI4736 and tremelimumab. There are three main subtypesof NSCLC: squamous cell carcinoma, adenocarcinoma, and large cell(undifferentiated) carcinoma. Other subtypes include adenosquamouscarcinoma and sarcomatoid carcinoma. NSCLC may comprise a mutation inKRAS or in the Epidermal Growth Factor receptor. Such mutations areknown in the art and described, for example, by Riely et al., Proc AmThorac Soc. 2009 Apr. 15; 6(2):201-5, which is incorporated herein byreference.

In addition, provided herein are methods for treating cancer orneoplastic growths using MEDI4736 and tremelimumab. As used herein“cancer” refers to a disease caused by an uncontrolled division ofabnormal cells. Examples of cancer include prostate cancer, breastcancer, triple negative breast cancer, colon cancer, lung cancer, NSCLC,head and neck cancer, melanoma, gastric cancer, pancreatic cancer,ovarian cancer, renal cell carcinoma, and hepatic cancer.

The methods provided include administering an effective amount ofMEDI4736 or an antigen-binding fragment thereof and tremelimumab or anantigen-binding fragment thereof.

By “MEDI4736” is meant an antibody or antigen binding fragment thereofthat selectively binds a PD-L1 polypeptide and comprises at least aportion of a light chain variable region comprising the amino acidsequence of SEQ ID NO:1 and/or at least a portion of a heavy chainvariable region comprising the amino acid sequence of SEQ ID NO:2.

Information regarding MEDI4736 (or antigen-binding fragments thereof)for use in the methods provided herein can be found in U.S. Pat. No.8,779,108, the disclosure of which is incorporated herein by referencein its entirety. The fragment crystallizable (Fc) domain of MEDI4736contains a triple mutation in the constant domain of the IgG1 heavychain that reduces binding to the complement component C1q and the Fcγreceptors responsible for mediating antibody-dependent cell-mediatedcytotoxicity (ADCC). MEDI4736 is selective for PD-L1 and blocks thebinding of PD-L1 to the PD-1 and CD80 receptors. MEDI4736 can relievePD-L1-mediated suppression of human T-cell activation in vitro andinhibits tumor growth in a xenograft model via a T-cell dependentmechanism.

MEDI4736 for use in the methods provided herein comprises a heavy chainand a light chain or a heavy chain variable region and a light chainvariable region. In a specific aspect, MEDI4736 or an antigen-bindingfragment thereof for use in the methods provided herein comprises alight chain variable region comprising the amino acid sequence of SEQ IDNO:1 and a heavy chain variable region comprising the amino acidsequence of SEQ ID NO:2. In a specific aspect, MEDI4736 or anantigen-binding fragment thereof for use in the methods provided hereincomprises a heavy chain variable region and a light chain variableregion, wherein the heavy chain variable region comprises theKabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs:3-5, andwherein the light chain variable region comprises the Kabat-definedCDR1, CDR2, and CDR3 sequences of SEQ ID NOs:6-8. Those of ordinaryskill in the art would easily be able to identify Chothia-defined,Abm-defined or other CDR definitions known to those of ordinary skill inthe art. In a specific aspect, MEDI4736 or an antigen-binding fragmentthereof for use in the methods provided herein comprises the variableheavy chain and variable light chain CDR sequences of the 2.14H9OPTantibody as disclosed in U.S. Pat. No. 8,779,108, which is hereinincorporated by reference in its entirety.

By “Tremelimumab” is meant an antibody or antigen binding fragmentthereof that selectively binds a CTLA4 polypeptide and comprises atleast a portion of a light chain variable region comprising the aminoacid sequence of SEQ ID NO:9 and/or at least a portion of a heavy chainvariable region comprising the amino acid sequence of SEQ ID NO:10.Exemplary anti-CTLA4 antibodies are described for example at U.S. Pat.Nos. 6,682,736; 7,109,003; 7,123,281; 7,411,057; 7,824,679; 8,143,379;7,807,797; and 8,491,895 (Tremelimumab is 11.2.1, therein), which areherein incorporated by reference. Tremelimumab is an exemplaryanti-CTLA4 antibody. Tremelimumab sequences are provided in the sequencelisting below.

Information regarding tremelimumab (or antigen-binding fragmentsthereof) for use in the methods provided herein can be found in U.S.Pat. No. 6,682,736 (where it is referred to as 11.2.1, the disclosure ofwhich is incorporated herein by reference in its entirety. Tremelimumab(also known as CP-675,206, CP-675, CP-675206, and ticilimumab) is ahuman IgG2 monoclonal antibody that is highly selective for CTLA4 andblocks binding of CTLA4 to CD80 (B7.1) and CD86 (B7.2). It has beenshown to result in immune activation in vitro and some patients treatedwith tremelimumab have shown tumor regression.

Tremelimumab and antigen-binding fragments thereof for use in themethods provided herein comprises a heavy chain and a light chain or aheavy chain variable region and a light chain variable region. In aspecific aspect, tremelimumab or an antigen-binding fragment thereof foruse in the methods provided herein comprises a light chain variableregion comprising the amino acid sequence of SEQ ID NO:9 and a heavychain variable region comprising the amino acid sequence of SEQ IDNO:10. In a specific aspect, tremelimumab or an antigen-binding fragmentthereof for use in the methods provided herein comprises a heavy chainvariable region and a light chain variable region, wherein the heavychain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3sequences of SEQ ID NOs:11-13, and wherein the light chain variableregion comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQID NOs:14-16. Those of ordinary skill in the art would easily be able toidentify Chothia-defined, Abm-defined or other CDR definitions known tothose of ordinary skill in the art. In a specific aspect, tremelimumabor an antigen-binding fragment thereof for use in the methods providedherein comprises or the variable heavy chain and variable light chainCDR sequences of the 11.2.1 antibody as disclosed in U.S. Pat. No.6,682,736, which is herein incorporated by reference in its entirety.

The term “antigen binding fragment” refers to a portion of an intactantibody and/or refers to the antigenic determining variable regions ofan intact antibody. It is known that the antigen binding function of anantibody can be performed by fragments of a full-length antibody.Examples of antibody fragments include, but are not limited to, Fab,Fab′, F(ab′)2, and Fv fragments, linear antibodies, single chainantibodies, diabodies, and multispecific antibodies formed from antibodyfragments.

In certain aspects, a patient presenting with a NSCLC is administeredMEDI4736 or an antigen-binding fragment thereof and tremelimumab or anantigen-binding fragment thereof. MEDI4736 or an antigen-bindingfragment thereof and tremelimumab or an antigen-binding fragment thereofcan be administered only once or infrequently while still providingbenefit to the patient. In further aspects the patient is administeredadditional follow-on doses. Follow-on doses can be administered atvarious time intervals depending on the patient's age, weight, clinicalassessment, tumor burden, and/or other factors, including the judgmentof the attending physician.

The intervals between doses of MEDI4736 or an antigen-binding fragmentthereof can be every four weeks. The intervals between doses oftremelimumab or an antigen-binding fragment thereof can be every fourweeks. The intervals between doses of tremelimumab or an antigen-bindingfragment thereof can be every twelve weeks. The intervals between dosesof tremelimumab or an antigen-binding fragment thereof can be every fourweeks for six cycles and then every twelve weeks.

In certain aspects, MEDI4736 or an antigen-binding fragment thereof isadministered about as frequently as tremelimumab or an antigen-bindingfragment thereof. In certain aspects, MEDI4736 or an antigen-bindingfragment thereof is administered about three times as frequently astremelimumab or an antigen-binding fragment thereof.

In some embodiments, at least two doses of MEDI4736 or anantigen-binding fragment thereof and tremelimumab or an antigen-bindingfragment thereof are administered to the patient. In some embodiments,at least three doses, at least four doses, at least five doses, at leastsix doses, at least seven doses, at least eight doses, at least ninedoses, at least ten doses, or at least fifteen doses or more can beadministered to the patient. In some embodiments, MEDI4736 or anantigen-binding fragment thereof is administered over a four-weektreatment period, over an eight-week treatment period, over asixteen-week treatment period, over a twenty-week treatment period, overa twenty-four-week treatment period, or over a one-year or moretreatment period. In some embodiments, tremelimumab or anantigen-binding fragment thereof is administered over a four-weektreatment period, over an eight-week treatment period, over atwelve-week treatment period, over a sixteen-week treatment period, overa twenty-week treatment period, over a twenty-four-week treatmentperiod, over a thirty-six-week treatment period, over a forty-eight-weektreatment period, or over a one-year or more treatment period.

In some embodiments, MEDI4736 or an antigen-binding fragment thereof andtremelimumab or an antigen-binding fragment thereof are administered onthe same day. In some embodiments, MEDI4736 or an antigen-bindingfragment thereof is administered at the same time as tremelimumab or anantigen-binding fragment thereof. In other embodiments, MEDI4736 or anantigen-binding fragment thereof is administered about 1 hour followingadministration of tremelimumab or an antigen-binding fragment thereof.

The amount of MEDI4736 or an antigen-binding fragment thereof and theamount of tremelimumab or an antigen-binding fragment thereof to beadministered to the patient will depend on various parameters such asthe patient's age, weight, clinical assessment, tumor burden and/orother factors, including the judgment of the attending physician.

In certain aspects the patient is administered one or more doses ofMEDI4736 or an antigen-binding fragment thereof wherein the dose isabout 1 mg/kg. In certain aspects the patient is administered one ormore doses of MEDI4736 or an antigen-binding fragment thereof whereinthe dose is about 3 mg/kg. In certain aspects the patient isadministered one or more doses of MEDI4736 or an antigen-bindingfragment thereof wherein the dose is about 10 mg/kg. In certain aspectsthe patient is administered one or more doses of MEDI4736 or anantigen-binding fragment thereof wherein the dose is about 15 mg/kg. Incertain aspects the patient is administered one or more doses ofMEDI4736 or an antigen-binding fragment thereof wherein the dose isabout 20 mg/kg.

In certain aspects the patient is administered at least two doses ofMEDI4736 or an antigen-binding fragment thereof wherein the dose isabout 1 mg/kg. In certain aspects the patient is administered at leasttwo doses of MEDI4736 or an antigen-binding fragment thereof wherein thedose is about 3 mg/kg. In certain aspects the patient is administered atleast two doses of MEDI4736 or an antigen-binding fragment thereofwherein the dose is about 10 mg/kg. In certain aspects the patient isadministered at least two doses of MEDI4736 or an antigen-bindingfragment thereof wherein the dose is about 15 mg/kg. In certain aspectsthe patient is administered at least two doses of MEDI4736 or anantigen-binding fragment thereof wherein the dose is about 20 mg/kg. Insome embodiments, the at least two doses are administered about fourweeks apart.

In certain aspects the patient is administered at least three doses ofMEDI4736 or an antigen-binding fragment thereof wherein the dose isabout 1 mg/kg. In certain aspects the patient is administered at leastthree doses of MEDI4736 or an antigen-binding fragment thereof whereinthe dose is about 3 mg/kg. In certain aspects the patient isadministered at least three doses of MEDI4736 or an antigen-bindingfragment thereof wherein the dose is about 10 mg/kg. In certain aspectsthe patient is administered at least three doses of MEDI4736 or anantigen-binding fragment thereof wherein the dose is about 15 mg/kg. Incertain aspects the patient is administered at least three doses ofMEDI4736 or an antigen-binding fragment thereof wherein the dose isabout 20 mg/kg. In some embodiments, the at least three doses areadministered about four weeks apart.

In certain aspects the patient is administered one or more doses oftremelimumab or an antigen-binding fragment thereof wherein the dose isabout 1 mg/kg. In certain aspects the patient is administered one ormore doses of tremelimumab or an antigen-binding fragment thereofwherein the dose is about 3 mg/kg. In certain aspects the patient isadministered one or more doses of tremelimumab or an antigen-bindingfragment thereof wherein the dose is about 10 mg/kg.

In certain aspects the patient is administered at least two doses oftremelimumab or an antigen-binding fragment thereof wherein the dose isabout 1 mg/kg. In certain aspects the patient is administered at leasttwo doses of tremelimumab or an antigen-binding fragment thereof whereinthe dose is about 3 mg/kg. In certain aspects the patient isadministered at least two doses of tremelimumab or an antigen-bindingfragment thereof wherein the dose is about 10 mg/kg. In someembodiments, the at least two doses are administered about four weeksapart. In some embodiments, the at least two doses are administeredabout twelve weeks apart.

In certain aspects the patient is administered at least three doses oftremelimumab or an antigen-binding fragment thereof wherein the dose isabout 1 mg/kg. In certain aspects the patient is administered at leastthree doses of tremelimumab or an antigen-binding fragment thereofwherein the dose is about 3 mg/kg. In certain aspects the patient isadministered at least three doses of tremelimumab or an antigen-bindingfragment thereof wherein the dose is about 10 mg/kg. In someembodiments, the at least three doses are administered about four weeksapart. In some embodiments, the at least three doses are administeredabout twelve weeks apart.

In certain aspects, administration of MEDI4736 or an antigen-bindingfragment thereof and/or tremelimumab or an antigen-binding fragmentaccording to the methods provided herein is through parenteraladministration. For example, MEDI4736 or an antigen-binding fragmentthereof and/or tremelimumab or an antigen-binding fragment can beadministered by intravenous infusion or by subcutaneous injection. Insome embodiments, the administration is by intravenous infusion.

In certain aspects, 1 mg/kg of MEDI4736 or an antigen-binding fragmentthereof and 1 mg/kg of tremelimumab or an antigen-binding fragmentthereof are administered to a patient. In certain aspects, 1 mg/kg ofMEDI4736 or an antigen-binding fragment thereof and 3 mg/kg oftremelimumab or an antigen-binding fragment thereof are administered toa patient. In certain aspects, 1 mg/kg of MEDI4736 or an antigen-bindingfragment thereof and 10 mg/kg of tremelimumab or an antigen-bindingfragment thereof are administered to a patient.

In certain aspects, 3 mg/kg of MEDI4736 or an antigen-binding fragmentthereof and 1 mg/kg of tremelimumab or an antigen-binding fragmentthereof are administered to a patient. In certain aspects, 3 mg/kg ofMEDI4736 or an antigen-binding fragment thereof and 3 mg/kg oftremelimumab or an antigen-binding fragment thereof are administered toa patient. In certain aspects, 3 mg/kg of MEDI4736 or an antigen-bindingfragment thereof and 10 mg/kg of tremelimumab or an antigen-bindingfragment thereof are administered to a patient.

In certain aspects, 10 mg/kg of MEDI4736 or an antigen-binding fragmentthereof and 1 mg/kg of tremelimumab or an antigen-binding fragmentthereof are administered to a patient. In certain aspects, 10 mg/kg ofMEDI4736 or an antigen-binding fragment thereof and 3 mg/kg oftremelimumab or an antigen-binding fragment thereof are administered toa patient. In certain aspects, 10 mg/kg of MEDI4736 or anantigen-binding fragment thereof and 10 mg/kg of tremelimumab or anantigen-binding fragment thereof are administered to a patient.

In certain aspects, 15 mg/kg of MEDI4736 or an antigen-binding fragmentthereof and 1 mg/kg of tremelimumab or an antigen-binding fragmentthereof are administered to a patient. In certain aspects, 15 mg/kg ofMEDI4736 or an antigen-binding fragment thereof and 3 mg/kg oftremelimumab or an antigen-binding fragment thereof are administered toa patient. In certain aspects, 15 mg/kg of MEDI4736 or anantigen-binding fragment thereof and 10 mg/kg of tremelimumab or anantigen-binding fragment thereof are administered to a patient.

In certain aspects, 20 mg/kg of MEDI4736 or an antigen-binding fragmentthereof and 1 mg/kg of tremelimumab or an antigen-binding fragmentthereof are administered to a patient. In certain aspects, 20 mg/kg ofMEDI4736 or an antigen-binding fragment thereof and 3 mg/kg oftremelimumab or an antigen-binding fragment thereof are administered toa patient. In certain aspects, 20 mg/kg of MEDI4736 or anantigen-binding fragment thereof and 10 mg/kg of tremelimumab or anantigen-binding fragment thereof are administered to a patient.

The methods provided herein can decrease, retard or stabilize tumorgrowth. In some aspects the reduction or retardation can bestatistically significant. A reduction in tumor growth can be measuredby comparison to the growth of patient's tumor at baseline, against anexpected tumor growth, against an expected tumor growth based on a largepatient population, or against the tumor growth of a control population.In certain aspects, a tumor response is measured using the ResponseEvaluation Criteria in Solid Tumors (RECIST).

In certain aspects, a tumor response is detectable at week 8. In certainaspects, a tumor response is detectable at week 33. In certain aspects,a tumor response is detectable at week 50.

In certain aspects, a tumor response is detectable after administrationof administration of two doses of MEDI4736 or an antigen-bindingfragment thereof and two doses of tremelimumab or an antigen-bindingfragment thereof. In certain aspects, a tumor response is detectableafter administration of administration of eight doses of MEDI4736 or anantigen-binding fragment thereof and seven doses of tremelimumab or anantigen-binding fragment thereof. In certain aspects, a tumor responseis detectable after administration of administration of thirteen dosesof MEDI4736 or an antigen-binding fragment thereof and nine doses oftremelimumab or an antigen-binding fragment thereof.

In certain aspects, a patient achieves disease control (DC). Diseasecontrol can be a complete response (CR), partial response (PR), orstable disease (SD).

A “complete response” (CR), a “partial response” (PR), and “stabledisease” (SD) can be determined as defined in Table 1 below.

In certain aspects, administration of MEDI4736 or an antigen-bindingfragment thereof can increase progression-free survival (PFS).

In certain aspects, administration of MEDI4736 or an antigen-bindingfragment thereof can increase overall survival (OS).

In some embodiments, the patient has previously received treatment withat least one chemotherapeutic agent. In some embodiments, the patienthas previously received treatment with at least two chemotherapeuticagents. The chemotherapeutic agent can be, for example, and withoutlimitation, Vemurafenib, Erlotinib, Afatinib, Cetuximab, Carboplatin,Bevacizumab, Erlotinib, Gefitinib, and/or Pemetrexed.

In some embodiments, the NSCLC is refractory or resistant to at leastone chemotherapeutic agent. In some embodiments, the tumor is refractoryor resistant to at least two chemotherapeutic agents. The tumor can berefractory or resistant to one or more of, for example, and withoutlimitation, Vemurafenib, Erlotinib, Afatinib, Cetuximab, Carboplatin,Bevacizumab, Erlotinib, Gefitinib, and/or Pemetrexed. In someembodiments, the NSCLC is negative for PD-L1. In some embodiments, theNSCLC is positive for PD-L1.

In some embodiments, the patient has an Eastern Cooperative OncologyGroup (ECOG) (Oken M M, et al. Am. J. Clin. Oncol. 5: 649-55 (1982))performance status of 0 or 1 prior to the administration of MEDI4736 oran antigen-binding fragment thereof and tremelimumab or anantigen-binding fragment thereof.

According to the methods provided herein, administration of MEDI4736 oran antigen-binding fragment thereof and tremelimumab or anantigen-binding fragment thereof can result in desirable pharmacokineticparameters as shown in some early data. Total drug exposure can beestimated using the “area under the curve” (AUC). “AUC (tau)” refers toAUC from time 0 to time T, the dosing interval, whereas “AUC (inf)”refers to the AUC until infinite time. The administration can produceAUC (tau) of about 600 to about 3,000 μg/mL*day of MEDI4736 orantigen-binding fragment thereof and about 250 to about 350 μg/mL*day oftremelimumab or antigen-binding fragment thereof. The administration canproduce a maximum observed concentration (Cmax) of about 60 to about 300μg/mL MEDI4736 or antigen-binding fragment thereof and of about 25 toabout 35 μg/mL tremelimumab or antigen-binding fragment thereof. Theadministration can produce a C trough (minimum plasma drugconcentration) of about 5 to about 40 μg/mL MEDI4736 or antigen-bindingfragment thereof and about 4 to about 6 μg/mL tremelimumab orantigen-binding fragment thereof.

As provided herein, MEDI4736 or an antigen-binding fragment thereof canalso decrease free (soluble) PD-L1 levels. Free (soluble) PD-L1 refersto PD-L1 that is not bound (e.g., by MEDI4736). In some embodiments,PD-L1 levels are reduced by at least 65%. In some embodiments, PD-L1levels are reduced by at least 80%. In some embodiments, PD-L1 levelsare reduced by at least 90%. In some embodiments, PD-L1 levels arereduced by at least 95%. In some embodiments, PD-L1 levels are reducedby at least 99%. In some embodiments, PD-L1 levels are not detectablefollowing administration of MEDI4736 or an antigen-binding fragmentthereof and tremelimumab or an antigen-binding fragment thereof.

In some embodiments, PD-L1 levels are reduced by at least 65% after asingle administration of MEDI4736 or an antigen-binding fragmentthereof. In some embodiments, PD-L1 levels are reduced by at least 80%after a single administration of MEDI4736 or an antigen-binding fragmentthereof. In some embodiments, PD-L1 levels are reduced by at least 90%after a single administration of MEDI4736 or an antigen-binding fragmentthereof. In some embodiments, PD-L1 levels are reduced by at least 95%after a single administration of MEDI4736 or an antigen-binding fragmentthereof In some embodiments, PD-L1 levels are reduced by at least 99%after a single administration of MEDI4736 or an antigen-binding fragmentthereof. In some embodiments, PD-L1 levels are not detectable followinga single administration of MEDI4736 or an antigen-binding fragmentthereof.

In some embodiments, PD-L1 levels are reduced by at least 65% afteradministration of two doses of MEDI4736 or an antigen-binding fragmentthereof. In some embodiments, PD-L1 levels are reduced by at least 80%after administration of two doses of MEDI4736 or an antigen-bindingfragment thereof. In some embodiments, PD-L1 levels are reduced by atleast 90% after administration of two doses of MEDI4736 or anantigen-binding fragment thereof. In some embodiments, PD-L1 levels arereduced by at least 95% after administration of two doses of MEDI4736 oran antigen-binding fragment thereof. In some embodiments, PD-L1 levelsare reduced by at least 99% after administration of two doses ofMEDI4736 or an antigen-binding fragment thereof. In some embodiments,PD-L1 levels are not detectable following administration of two doses ofMEDI4736 or an antigen-binding fragment thereof.

Treatment of a patient with a solid tumor using both MEDI4736 or anantigen-binding fragment thereof and tremelimumab or an antigen-bindingfragment thereof (i.e., co-therapy) as provided herein can result in ansynergistic effect. As used herein, the term “synergistic” refers to acombination of therapies (e.g., a combination of MEDI4736 or anantigen-binding fragment thereof and tremelimumab or an antigen-bindingfragment thereof) which is more effective than the additive effects ofthe single therapies.

A synergistic effect of a combination of therapies (e.g., a combinationof a MEDI4736 or an antigen-binding fragment thereof and tremelimumab oran antigen-binding fragment thereof) permits the use of lower dosages ofone or more of the therapeutic agents and/or less frequentadministration of said therapeutic agents to a patient with a solidtumor. The ability to utilize lower dosages of therapeutic agents and/orto administer said therapies less frequently reduces the toxicityassociated with the administration of said therapies to a subjectwithout reducing the efficacy of said therapies in the treatment of asolid tumor. In addition, a synergistic effect can result in improvedefficacy of therapeutic agents in the management, treatment, oramelioration of an solid tumor. The synergistic effect of a combinationof therapeutic agents can avoid or reduce adverse or unwanted sideeffects associated with the use of either single therapy.

In co-therapy, MEDI4736 or an antigen-binding fragment thereof can beoptionally included in the same pharmaceutical composition as thetremelimumab or an antigen-binding fragment thereof, or may be includedin a separate pharmaceutical composition. In this latter case, thepharmaceutical composition comprising MEDI4736 or an antigen-bindingfragment thereof is suitable for administration prior to, simultaneouslywith, or following administration of the pharmaceutical compositioncomprising tremelimumab or an antigen-binding fragment thereof. Incertain instances, the MEDI4736 or an antigen-binding fragment thereofis administered at overlapping times as tremelimumab or anantigen-binding fragment thereof in a separate composition.

Subjects suffering from lung cancer (e.g., non-small cell lung cancer)may be tested for PD-L1 polynucleotide or polypeptide expression in thecourse of selecting a treatment method. Patients identified as havingtumors that are negative for PD-L1 (e.g., as defined by Ct or IHC-Mscore) or by having reduced or undetectable levels of PD-L1 relative toa reference level are identified as responsive to treatment with acombination of an anti-PD-L1 antibody and tremelimumab. Such patientsare administered an MEDI4736, or an antigen-binding fragment thereof incombination with tremelimumab or an antigen-binding fragment thereof.

EXAMPLES Example 1: Patients and Methods

(a) Subjects

Subjects in this study are required to be 18 years of age or older andhave histologically- or cytologically-confirmed non-small cell lungcancer (NSCLC; squamous and non-squamous), with at least one measurablelesion according to Response Evaluation Criteria in Solid Tumors(RECIST) guidelines v1.1, which is herein incorporated by reference inits entirety.

For both the dose-escalation and dose-expansion phases, cohort-specificprior immunotherapy requirements are as follows: a) immunotherapy-naïvecohort: must have no prior exposure to immunotherapy, such as, but notlimited to, other anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibodiesexcluding vaccines; and b) immunotherapy-pretreated cohort: must havehad prior exposure to immunotherapy, such as, but not limited to, otheranti-CTLA-4, anti-PD-1, or anti-PD-L1 antibodies excluding vaccinesgreater than 28 days prior to the first dose of MEDI4736 andtremelimumab.

The subjects are also required to have failed to respond to standardtreatment, relapsed following standard treatment, declined standardtreatment, or have not been eligible for standard treatment. Subjectswill have an Eastern Cooperative Oncology Group (ECOG) performancestatus of 0-1.

Subjects with central nervous system (CNS) metastases must beasymptomatic at day 1 of the study. In addition, by day 1, there must beat least 28 weeks without progression of CNS metastases as evidenced bymagnetic resonance imaging (MRI)/computed tomography (CT) after last dayof treatment with radiation and at least 14 days since last dose ofcorticosteroids.

The subjects are also required to have adequate organ (hepatic andrenal) and marrow function. Adequate organ and marrow function aredefined as: hemoglobin ≥9 g/dL; absolute neutrophil count ≥1,500/mm³;platelet count ≥100,000/mm³; total bilirubin ≤1.5×upper limit of normal(ULN), unless associated with Gilbert's syndrome or liver metastasis(for these subjects, baseline total bilirubin must be ≤3.0 mg/dL);alanine aminotransferase (ALT) and aspartate aminotransferase (AST) mustbe ≤2.5×ULN unless associated with hepatic metastases (for thesesubjects, ALT and AST must be ≤5×ULN); and serum creatinine ≤2.0 mg/dL.

Subjects are not able to participate if they are on any concurrentchemotherapy, immunotherapy, biologic, or hormonal therapy for cancertreatment. Subjects are not able to participate if they have taken anyinvestigational anticancer therapy within 28 days prior to the firstdose of MEDI4736 and tremelimumab. Subjects are not able to participateif they have any prior Grade ≥3 immune-related adverse event (irAE)while receiving immunotherapy, including anti-CTLA-4 treatment, or anyunresolved irAE >Grade 1. Subjects are also not able to participate ifthey have undergone a major surgical procedure (as defined by theinvestigator) within 28 days prior to the first dose of MEDI4736 andtremelimumab or if they are still recovering from prior surgery.Subjects are also not able to participate if they have unresolvedtoxicities from prior anticancer therapy, defined as having not resolvedto National Cancer Institute Common Terminology Criteria for AdverseEvents (NCI CTCAE) v4.03 Grade 0 or 1 with the exception of alopecia andlaboratory values listed per the inclusion criteria. Subjects withirreversible toxicity that is not reasonably expected to be exacerbatedby MEDI4736 and tremelimumab may be included. Subjects are also excludedif they are currently using, or have used immunosuppressive medicationwithin 14 days before the first dose of MEDI4736 and tremelimumab withthe exceptions of intranasal and inhaled corticosteroids or systemiccorticosteroids at physiologic doses not to exceed 10 mg/day ofprednisone or equivalent.

Subjects are not able to participate if they have active or priorautoimmune disease, including inflammatory bowel disease,diverticulitis, irritable bowel disease, celiac disease, Wegenersyndrome, and Hashimoto syndrome, within the past 3 years, except forvitiligo, alopecia, Grave's disease, or psoriasis not requiring systemictreatment (within the past 3 years). Subjects are also not able toparticipate if they have a history of primary immunodeficiency ortuberculosis, if they have known active or chronic viral hepatitis A, B,or C; if they have human immunodeficiency virus (HIV); other activeserious illnesses or uncontrolled inter-current illnesses; have receivedlive, attenuated vaccine within 28 days prior to the first dose ofMEDI4736 and tremelimumab; have other invasive malignancy within 5years; or known allergy or hypersensitivity to study drug formulations.

Subjects are also not able to participate if they have advanced NSCLCwith tumors harboring anaplastic lymphoma receptor tyrosine kinase (ALK)gene rearrangements or epidermal growth factor receptor(EGFR)-sensitizing mutations and have not received appropriate tyrosinekinase inhibitor (TM) therapy. These subjects can be enrolled afterdocumented progression or intolerance to appropriate TKIs.

(b) Design of the Study

The study is an open-label Phase 1b study of the combination of MEDI4736and tremelimumab (FIG. 1 ). Key study criteria for cohorts is shown atFIG. 11 . The study will enroll approximately 36 subjects in the doseescalation phase and in the dose-expansion phase and a minimum of 20subjects each in immunotherapy-naïve and immunotherapy-pretreatedcohorts. The maximum tolerated dose (MTD) or highest protocol-defineddose for each agent in the absence of exceeding the MTD determined forthe immunotherapy-naïve cohort during the dose-escalation phase willserve as the starting dose for the subjects enrolled in theimmunotherapy-pretreated cohort as part of the dose-escalation phase.Does exploration for the immunotherapy-pretreated cohort will beconducted in parallel with the dose-expansion phase for theimmunotherapy-naïve cohort.

Dose-Escalation Phase

Immunotherapy-Naïve Cohort

In the dose-escalation phase of the study, MEDI4736 and tremelimumabwill be administered initially in sequential cohorts of 3-6 subjects whoare immunotherapy-naïve with each subject receiving tremelimumab Q4W for6 doses and every 12 weeks (Q12W) for 3 doses (i.e., tremelimumab Dose 7given at 4 weeks from Dose 6 and Dose 8 given at 12 weeks from Dose 7)and MEDI4736 Q4W for 13 doses via IV infusion for a total of one year(FIG. 2 ). Each cohort will enroll a minimum of 3 subjects, according toa standard 3+3 design and a modified zone-based design. Subjects in thefirst cohort (Cohort 1) will receive a dose of 3 mg/kg MEDI4736 and 1mg/kg of tremelimumab. If ≥2 dose limiting toxicities (DLTs) areobserved in the first dose cohort, the starting dose will bede-escalated per FIG. 1 . If no more than 1 out of 6 subjectsexperiences a DLT in a given dose cohort, dose-escalation will continue.

Subsequent cohorts will receive tremelimumab administered Q4W for 6doses followed by Q12W for 3 doses and MEDI4736 administered Q4W for 13doses until an MTD or the highest protocol-defined dose for each agentin the absence of exceeding the MTD is identified.

The expansion phase for the immunotherapy-naïve cohort (see FIG. 1 )will begin once the MTD or highest protocol-defined dose for each agentin the absence of exceeding the MTD is determined in theimmunotherapy-naïve subjects during the dose-escalation phase.Additional dose(s) from the intermediate zone-based cohort(s) that donot exceed the MTD can be evaluated in the expansion phase based onevaluation of PK and pharmacodynamics, safety and efficacy parameters inthe immunotherapy-naïve cohort from the dose-expansion phase.

Immunotherapy-Pretreated Cohort

The MTD or highest protocol-defined dose for each agent in the absenceof exceeding the MTD determined for the immunotherapy-naïve cohort (seeFIG. 1 ) during the dose escalation phase will serve as the startingdose for subjects enrolled in the immunotherapy-pretreated cohort aspart of the dose-escalation phase. The dose exploration for theimmunotherapy-pretreated cohort using 3+3 design will be conducted inparallel with the dose-expansion phase for the immunotherapy-naïvecohort. The dose-expansion phase for the immunotherapy-pretreated cohortcan begin once the MTD or highest protocol-defined dose for each agentin the absence of exceeding the MTD is determined in theimmunotherapy-pretreated subjects during the dose-escalation phase.Additional dose(s) from the intermediate zone-based cohort(s) that donot exceed the MTD can be evaluated in the dose-expansion phase based onevaluation of PK and pharmacodynamics, safety and efficacy parameters inthe immunotherapy-pretreated cohort from the dose-expansion phase.

Dose-Expansion Phase

Two dose-expansion cohorts will be used: immunotherapy-naïve andimmunotherapy-pretreated (see FIG. 1 ). The MTD or highestprotocol-defined dose for each agent in the absence of exceeding the MTDidentified during the dose-escalation phase will be used for bothcohorts in the dose-expansion phase. In addition, dose(s) from theintermediate zone-based cohort(s) that do not exceed the MTD can beincluded as an additional dose(s) for the immunotherapy-pretreated andimmunotherapy-naïve cohorts in the dose-expansion phase based onemerging subject data, including safety, PK, pharmacodynamics,biomarker, and response as well as data present from ongoing trials.

Initially approximately 20 subjects with NSCLC will be enrolled in eachof the immunotherapy-naïve cohort and the immunotherapy-pretreatedcohort. Additional subjects, up to a total of 60 subjects each can beenrolled for the immunotherapy-naïve cohort in the dose-expansion phasedependent on emerging subject data, including safety, PK,pharmacodynamics, biomarker, and response as well as data present fromongoing trials.

Treatment Regimen

Subjects will be treated in either the dose-escalation or thedose-expansion phase of the study. In the dose-escalation anddose-expansion phases of the study, tremelimumab will be administeredevery four weeks (Q4W) for 6 doses followed by every twelve weeks (Q12W)for 3 doses in which Dose 7 is given 4 weeks after Dose 6 and Dose 8 isgiven 12 weeks after Dose 7. MEDI4736 will be administered Q4W for 13doses. Both agents will be administered via IV infusion for a total ofone year (FIG. 2 ).

Tremelimumab will be administered intravenously in 250 mL of 0.9% sodiumchloride. MEDI4736 will be administered intravenously in 250 ml of 0.9%sodium chloride. Tremelimumab will be administered first. MEDI4736infusion will start approximately 1 hour after the end of tremelimumabinfusion. In Cohort 1, the first IV infusion of tremelimumab will beapproximately 1 hour in duration and the first IV infusion of MEDI4736will be approximately 4 hours in duration; subsequent infusions forsubjects in this cohort and all infusions for the remaining cohorts willbe approximately 1 hour in duration.

Subjects who achieve and maintain disease control (DC) (i.e., completeresponse (CR), partial response (PR), or stable disease (SD)) through tothe end of the 12-month MEDI4736 and tremelimumab treatment period willenter follow-up. Upon evidence of progressive disease (PD) duringfollow-up, subjects may be re-administered MEDI4736 and tremelimumab forup to another 12 months with the same treatment guidelines followedduring the initial 12-month period if the subject has not received othertreatments for their disease and still meet inclusion and exclusioncriteria for the study protocol. Only one round of retreatment withMEDI4736 and tremelimumab will be allowed.

The study utilizes a 3+3 dose-escalation phase and will follow thescheme depicted in FIG. 3 . A minimum of three subjects will be enrolledin each dose cohort. If 0 out of the 3 patients in a dose cohort have adose limiting toxicity (DLT), the next dose-escalation cohort will bestarted. If 1 out of the 3 patients has a DLT, an additional 3 patientswill be enrolled in the same cohort. If no more than 1 of 6 subjectsexperiences a DLT, the next dose-escalation cohort will be started. If 2or more patients in a dose cohort experience a DLT during the evaluationperiod, then no further subjects will be enrolled in that dose cohort.

The maximum tolerated dose (MTD) is defined as the highest dose oftremelimumab or MEDI4736 within a cohort where no more than 1 of 6patients experiences a DLT. This is determined for both theimmunotherapy-naïve and pretreated cohorts during the dose-escalationphase. Patients in the expansion phase (immunotherapy-naïve andimmunotherapy-pretreated cohorts) will be treated at the MTD leveldetermined in the dose-escalation phase.

MEDI4736 and tremelimumab administration can be modified or discontinuedas a result of toxicities as described in FIGS. 10A and 10B. Dosemodifications will not be required for adverse events (AEs) that areclearly not attributed to MEDI4736 or tremelimumab (such as an accident)or for laboratory abnormalities that are not deemed to be clinicallysignificant.

(c) Pharmacokinetic, Anti-Tumor, Biomarker, Soluble Factor, and SafetyAssessments

Measurement of MEDI4736 and tremelimumab concentrations in serum will beperformed using a validated immunoassay.

Blood samples for pharmacokinetic assessment will be collected on thefollowing days during the dose-escalation phase: day 1 (pre-dose and endof infusion), day 8 (±1 day), day 15 (±1 day), day 29 (pre-dose and endof infusion; ±3 days), day 57 (pre-dose and end of infusion; ±3 days),day 85 (pre-dose and end of infusion; ±3 days), day 113 (pre-dose andend of infusion; ±3 days), day 141 (pre-dose and end of infusion; ±3days), day 169 (pre-dose and end of infusion; ±3 days), day 197(pre-dose and end of infusion; ±3 days; MEDI4736 only), day 225(pre-dose and end of infusion; ±3 days; MEDI4736 only), day 253(pre-dose and end of infusion; ±3 days), day 281 (pre-dose and end ofinfusion; ±3 days; MEDI4736 only), day 309 (pre-dose and end ofinfusion; ±3 days), day 337 (pre-dose and end of infusion; ±3 days), atthe end of treatment, 60 days after end of treatment, and 90 days afterend of treatment.

Blood samples for pharmacokinetic assessment will be collected on thefollowing days during the dose-expansion phase: day 1 (pre-dose and endof infusion), day 29 (±3 days), day 57 (±3 days), day 85 (±3 days), day113 (±3 days), day 141 (±3 days), day 169 (±3 days); day 197 (±3 days;MEDI4736 only), day 225 (±3 days; MEDI4736 only), day 253 (±3 days), day281 (±3 days; MEDI4736 only), day 309 (±3 days; MEDI4736 only), day 337(±3 days), at the end of treatment, 60 days after end of treatment, and90 days after end of treatment.

The presence of anti-drug antibodies (ADA) will be assessed on Day 1 andDays 29 (±3 days), 85 (±3 days), 141 (±3 days), 169 (±3 days), 253 (±3days), and 337 (±3 days), at the end of treatment, 60 days after the endof treatment, and 90 days after the end of treatment. Validatedelectrochemiluminescence assays using a Meso Scale Discovery platformwill be used for the determination of anti-MEDI4736 antibodies in humanserum and for determination of anti-tremelimumab antibodies in humanserum.

Blood samples will be collected for analysis of circulating solublefactors including soluble PD-L1 (sPD-L1). During the dose-escalationphase, levels of sPD-L1 will be assessed on day 1, day 8 (±1 day), day15 (±1 day), day 29 (±3 days), day 57 (±3 days), day 85 (±3 days), day113 (±3 days), day 141 (±3 days), day 169 (±3 days); day 197 (±3 days),day 225 (±3 days), day 253 (±3 days), day 281 (±3 days), day 309 (±3days), day 337 (±3 days), at the end of treatment, 60 days after end oftreatment, and 90 days after end of treatment. During the dose-expansionphase, levels of sPD-L1 will be assessed on day 1, day 29 (±3 days), day57 (±3 days), day 85 (±3 days), day 113 (±3 days), day 141 (±3 days),day 169 (±3 days); day 197 (±3 days), day 225 (±3 days), day 253 (±3days), day 281 (±3 days), day 309 (±3 days), day 337 (±3 days), at theend of treatment, 60 days after end of treatment, and 90 days after endof treatment.

Tumor assessments will be performed during screening (day −28 to day−1), at week 8 (day 50±3 days), and at week 33 (day 225±3 days) in thedose-escalation phase. Tumor assessments will be based on RECISTguidelines v1.1 with modifications and include the followingevaluations: physical examination (with photograph and measurement ofskin lesions as applicable), CT, or MRI scan of the chest, abdomen, andpelvis, and CT or MRI scan of the brain. Computed tomography or MRI scanof the brain is performed only at screening.

Assessments of anti-tumor activity are based on the measurement of tumorlesions, the evaluation of target lesions, the evaluation of non-targetlesions, and the appearance of new lesions.

Target Lesion Evaluation

For the evaluation of target lesions, complete response is defined asthe disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to <10mm (the sum may not be “0” if there are target nodes).

For the evaluation of target lesions, partial response is defined as atleast a 30% decrease in the sum of the diameters of target lesions,taking as reference the baseline sum diameters.

For the evaluation of target lesions, progressive disease is defined asat least a 20% increase in the sum of diameters of target lesions,taking as reference the smallest sum on study (this includes thebaseline sum if that is the smallest on study). In addition to therelative increase of 20%, the sum must also demonstrate an absoluteincrease of at least 5 mm. The appearance of one or more new lesions isalso considered progression.

For the evaluation of target lesions, stable disease (SD) is neithersufficient shrinkage to qualify for PR nor sufficient increase toqualify for PD, taking as reference the smallest sum of diameters whileon study.

Non-Target Lesion Evaluation

For the evaluation of non-target lesions, complete response (CR) isdefined as the disappearance of all non-target lesions. All lymph nodesmust be <10 mm in short axis.

For the evaluation of non-target lesions, non-competeresponse/non-progressive disease is defined as the persistence of onemore non-target lesions and/or maintenance of tumor marker level abovethe normal limits.

For the evaluation of non-target lesions, progressive disease is definedas the overall level of substantial worsening in non-target disease suchthat, even in presence of SD or PR in target disease, the overall tumorburden has increased sufficiently to merit discontinuation of therapy.In the absence of measurable disease, change in non-measurable diseasecomparable in magnitude to the increase that would be required todeclare PD for measurable disease.

New Lesion

The appearance of new lesions is considered PD according to RECISTguidelines v1.1. Considering the unique response kinetics that have beenobserved with immunotherapy, new lesions may not represent true diseaseprogression. In the absence of rapid clinical deterioration, subjectsmay continue to receive treatment with MEDI4736 and tremelimumab.

Overall Response

Confirmation of CR, PR, as well as PD is required by a repeat,consecutive assessment no less than 4 weeks from the date of firstdocumentation. The evaluation of overall response based on targetlesion, non-target lesion, and new lesion evaluation is determined as inTable 1 below.

TABLE 1 Evaluation of Overall Response New Target Lesions Non-targetlesions Lesions Overall Response Complete Complete Response No CompleteResponse Response No target lesion^(a) Complete Response No CompleteResponse Complete Not evaluable^(b) No Partial Response ResponseComplete Non-complete No Partial Response Response response/non-progressive disease Partial Response Non-progressive No Partial Responsedisease and not evaluable^(b) Stable Disease Non-progressive No StableDisease disease and not evaluable^(b) Not all evaluated Non-progressiveNo Not evaluable disease No target lesion^(a) Not all evaluated No Notevaluable No target lesion^(a) Non-complete No Non-completeresponse/non- response/non- progressive disease progressive diseaseProgressive Any Yes or No Progressive Disease Disease Any ProgressiveDisease Yes or No Progressive Disease Any Any Yes Progressive Disease Notarget lesion^(a) Unequivocal Yes or No Progressive Disease progressivedisease No target lesion^(a) Any Yes Progressive Disease ^(a)Defined asno target lesions at baseline. ^(b)Not evaluable is defined as eitherwhen no or only a subset of lesion measurements are made at anassessment.

Adverse events are monitored following administration of MEDI4736. Otherassessments include physical examination, vital sign monitoring, andlaboratory measurements.

Example 2: Results

(a) Enrollment and Follow-Up

Twelve subjects were treated with 3 subjects each in Cohort 1a (1 mg/kgtremelimumab and 3 mg/kg MEDI4736), Cohort 2a (1 mg/kg tremelimumab and10 mg/kg MEDI4736), Cohort 3a (1 mg/kg tremelimumab and 15 mg/kgMEDI4736), and Cohort 3b (3 mg/kg tremelimumab and 10 mg/kg MEDI4736).Two subjects in Cohort 1a (one subject withdrew consent after 2 doses ofboth agents) completed approximately 115 days of follow-up; Cohort 2asubjects completed approximately 56 days of follow-up; and subjects inCohorts 3a and 3b completed 28 days of follow up (FIG. 12 ).

(b) Pharmacokinetics

The pharmacokinetic data resulting from administration of MEDI4736 at 3mg/kg and 10 mg/kg (in combination with 1 mg/kg tremelimumab) issummarized in FIG. 4 . Individual PK parameters resulting from theadministration of MEDI4736 are shown in FIG. 8 . In this early data fromfirst dose, the average Cmax for subjects receiving 3 mg/kg MEDI4736 was67.36 μg/ml. The average AUCτ for subjects receiving 3 mg/kg MEDI4736was 625.3 μg/ml*day. The average C_(trough) for subjects receiving 3mg/kg MEDI4736 was 8.85 μg/ml. The average Cmax for subjects receiving10 mg/kg MEDI4736 was 266.7 μg/ml. The average AUCτ for subjectsreceiving 10 mg/kg MEDI4736 was 2860 μg/ml*day. The average C_(trough)for subjects receiving 10 mg/kg MEDI4736 was 35.65 μg/ml. MEDI4736exhibited a more than dose-proportional increase in AUC indicatingnon-linear PK. See FIG. 4 .

The pharmacokinetic data resulting from administration of tremelimumabat 1 mg/kg (in combination with either 3 mg/kg MEDI4736 or 10 mg/kgMEDI4736) is summarized in FIG. 5 . Individual PK parameters resultingfrom the administration of tremelimumab are shown in FIG. 9 .

The average Cmax for subjects receiving 1 mg/kg tremelimumab incombination with 3 mg/kg MEDI4736 was 27.07 μg/ml. The average Cmax forsubjects receiving 1 mg/kg tremelimumab in combination with 10 mg/kgMEDI4736 was 30.40 μg/ml.

The average AUCτ for subjects receiving 1 mg/kg tremelimumab incombination with 3 mg/kg MEDI4736 was 262.2 μg/ml*day. The average AUCτfor subjects receiving 1 mg/kg tremelimumab in combination with 10 mg/kgMEDI4736 was 338.8 μg/ml*day.

The average C_(trough) for subjects receiving 1 mg/kg tremelimumab incombination with 3 mg/kg MEDI4736 was 4.21 μg/ml. The average C_(trough)for subjects receiving 1 mg/kg tremelimumab in combination with 10 mg/kgMEDI4736 was 5.33 μg/ml.

(c) Soluble PD-L1 Assessment

The sPD-L1 data resulting from administration of MEDI4736 at 3 and 10mg/kg and tremelimumab at 1 mg/kg is shown in FIGS. 6 (absoluteconcentration), 7 and 8 (suppression, % of baseline). Following MEDI4736administration, complete sPD-L1 suppression was observed in 5 of 6subjects. In one subject, sPD-L1 suppression of approximately 65% wasobserved by the second dose of MEDI4736.

(d) Safety

Ten of twelve subjects reported a treatment-emergent adverse event(TEAE). The most frequently reported TEAEs were fatigue (41.7%; 5subjects), increased amylase (25.0%; 3 subjects), pruritus and upperrespiratory tract infection (16.7%; 2 subjects each). No subjectexperienced a dose-limiting toxicity. Nine of ten subjects whoexperienced TEAEs had events that were Grade 1 or 2 in severity. Onesubject (Cohort 2a) experienced Grade 3 increased aspartateaminotransferase (AST) and increased alanine aminotransferase (ALT) anda fatal (Grade 5) myasthenia gravis. Two of the twelve subjectsexperienced treatment-emergent serious adverse events (SAEs). Twosubjects discontinued treatment due to TEAEs. FIG. 13 shows relatedadverse events.

Early results showing change of tumor size from baseline are shown inFIG. 14 . Reductions in tumor size were seen in patients in the 1 mg/kg(T)+10 mg/kg (M), 1 mg/kg (T)+15 mg/kg (M) and 3 mg/kg (T)+10 mg/kg (M)groups.

This study demonstrates that MEDI4736 and tremelimumab have favorablepharmacokinetic properties and the combination of agents suppressessPD-L1. In addition, MEDI4736 is well tolerated in most of the subjectscurrently being treated.

Example 3: Phase 1b, Open-Label Study of MEDI4736 in Combination withTremelimumab in Patients with Advanced NSCLC

The inhibitory PD-L1 and CTLA-4 pathways play a major role incontrolling T cell activation. MEDI4736 (M) is a human IgG1 monoclonalantibody that blocks PD-L1 binding to PD-1 and CD-80. Tremelimumab (T)is a human IgG2 monoclonal antibody targeting CTLA-4. Both MEDI4736 andTremelimumab have demonstrated encouraging safety profiles and promisingclinical activity as single agents; as they block distinct interactionscontributing to immunosuppression, combination MEDI4736+Tremelimumabtherapy may provide greater antitumor activity compared with eitheragent alone in patients (pts) with advanced non-small cell lung cancer.

This Phase 1 study is assessing the safety/tolerability, antitumoractivity, pharmacokinetics (PK) and immunogenicity ofMEDI4736+Tremelimumab combination therapy in patients with advancedNSCLC. The study has dose-escalation and -expansion phases.

Results: As of Dec. 4, 2014, 61 patients have been treated (Table 2).

TABLE 2 Cohort Dose 1a  3 mg/kg M q4w + 1 mg/kg T 2a 10 mg/kg M q4w + 1mg/kg T 3a 15 mg/kg M q4w + 1 mg/kg T 3b 10 mg/kg M q4w + 3 mg/kg T 4 20 mg/kg M q4w + 1 mg/kg T 4a 15 mg/kg M q4w + 3 mg/kg T 5  15 mg/kg Mq4w + 10 mg/kg T 5a 20 mg/kg M q4w + 3 mg/kg T 6  20 mg/kg M q4w + 10mg/kg T 8  10 mg/kg M q2w + 1 mg/kg T 9  10 mg/kg M q2w + 3 mg/kg T 10 10 mg/kg M q2w + 10 mg/kg T MEDI4736 (M) + Tremelimumab (T) Q4W = every4 weeks; Q2W = every 2 weeks

Overall, the most frequent drug-related AEs for all grades (≥10% pts)were diarrhea, fatigue, pruritis, increased alanine transaminase (ALT)and amylase; that were manageable with standard treatment guidelinesincluding steroids. The most frequent ≥Grade 3 drug-related AEs (≥5%)across all patients were colitis, diarrhea, increased aspartateaminotransferase (AST) and ALT. Drug-related AEs leading todiscontinuation were colitis (6.6%), diarrhea (3.3%), pneumonitis(3.3%), increased AST (3.3%) and ALT (1.6%), cough (1.6%) and dyspnea(1.6%); there was 1 treatment-related death (polymyositis) in the 10mg/kg M q4w+1 mg/kg T cohort. Of 31 subjects with at least one 8 weekscan, the best overall response was reported in 8 patients (26%); stabledisease was reported in 11 pts (36%).

These promising results indicate that the MEDI4736+Tremelimumabcombination has a manageable safety profile and early clinical activity.

Results: As of Jan. 27, 2015, 74 patients across 10 cohorts have beentreated (Table 3).

TABLE 3 Demographics and Baseline Characteristics 1a 2a T 1 mg/kg T 1mg/kg M 3 mg/kg Q4W M 10 mg/kg Q4W Characteristic (N = 3) (N = 3) Age(years) n 3   3 Mean 73.7   67.3 SD 3.8   3.5 Median 72.0   67.0 (Min,Max) (71, 78) (64, 71) Sex Male 1 (33.3%) 2 (66.7%) Female 2 (66.7%) 1(33.3%) Baseline ECOG Status 0 0 (0.0%) 2 (66.7%) 1 3 (100%) 1 (33.3%)Histology Squamous 1 (33.3%) 0 (0.0%) Non-Squamous 2 (66.7%) 3 (100%)MISSING 0   0 Time since Initial n 3   3 Diagnosis to Study Treatment(Months) Mean 19.67   35.23 SD 13.27   8.71 Median 16.60   32.00 (Min,Max) (8.2, 34.2) (28.6, 45.1) Mutation Status EGFR 0 (0.0%) 0 (0.0%) ALK0 (0.0%) 0 (0.0%) KRAS 1 (33.3%) 1 (33.3%) No Mutation 0 (0.0%) 2(66.7%) Other 0 (0.0%) 0 (0.0%) Unknown 2 (66.7%) 0 (0.0%) MISSING 0   0Smoking History Never Smoked 1 (33.3%) 0 (0.0%) Former/Current Smoker 2(66.7%) 3 (100%) Number of Prior 1 1 (33.3%) 0 (0.0%) Systemic Regimens2 0 (0.0%) 0 (0.0%) 3 2 (66.7%) 2 (66.7%) 3a 3b 4 T 1 mg/kg T 3 mg/kg T1 mg/kg M 15 mg/kg Q4W M 10 mg/kg Q4W M 20 mg/kg Q4W Characteristic (N =18) (N = 3) (N = 18) Age (years) 18   3 18   66.2   63.7 64.2  7.1  16.77.7 66.5   54.0 66.0  (53, 78) (54, 83) (49, 78) Sex 9 (50.0%) 1 (33.3%)10 (55.6%) 9 (50.0%) 2 (66.7%) 8 (44.4%) Baseline ECOG Status 5 (27.8%)2 (66.7%) 5 (27.8%) 13 (72.2%) 1 (33.3%) 13 (72.2%) Histology 1 (5.6%) 0(0.0%) 1 (6.7%) 17 (94.4%) 3 (100%) 14 (93.3%) 0   0 3   Time sinceInitial 16   3 16   Diagnosis to Study Treatment (Months) 29.36   13.9018.98 32.20   10.57 14.74 15.40   11.40 16.55 (4.0, 127.8) (4.8, 25.5)(2.8, 68.2) Mutation Status 2 (11.1%) 0 (0.0%) 2 (13.3%) 0 (0.0%) 0(0.0%) 0 (0.0%) 1 (5.6%) 0 (0.0%) 1 (6.7%) 14 (77.8%) 3 (100%) 12(80.0%) 1 (5.6%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0   0 3  Smoking History 3 (16.7%) 1 (33.3%) 0 (0.0%) 15 (83.3%) 2 (66.7%) 18(100%) Number of Prior 4 (22.2%) 3 (100%) 4 (22.2%) Systemic Regimens 8(44.4%) 0 (0.0%) 6 (33.3%) 4 (22.2%) 0 (0.0%) 5 (27.8%) 4a 5 T 3 mg/kg T10 mg/kg M 15 mg/kg Q4W M 15 mg/kg Q4W Characteristic (N = 14) (N = 9)Age (years) n 14   9   Mean 68.6  63.7  SD 4.5 7.3 Median 69.0  65.0 (Min, Max) (59, 76) (54, 77) Sex Male 10 (71.4%) 4 (44.4%) Female 4(28.6%) 5 (55.6%) Baseline ECOG Status 0 6 (42.9%) 1 (11.1%) 1 8 (57.1%)8 (88.9%) Histology Squamous 1 (7.1%) 0 (0.0%) Non-Squamous 13 (92.9%) 9(100%) MISSING 0   0   Time since Initial n 13   9   Diagnosis to StudyTreatment (Months) Mean 20.72 26.89 SD 17.02 23.84 Median 14.10 19.70(Min, Max) (1.0, 53.3) (3.9, 81.7) Mutation Status EGFR 0 (0.0%) 2(22.2%) ALK 0 (0.0%) 0 (0.0%) KRAS 2 (14.3%) 3 (33.3%) No Mutation 8(57.1%) 3 (33.3%) Other 1 (7.1%) 1 (11.1%) Unknown 3 (21.4%) 0 (0.0%)MISSING 0   0   Smoking History Never Smoked 2 (14.3%) 1 (11.1%)Former/Current Smoker 12 (85.7%) 8 (88.9%) Number of Prior 1 4 (30.8%) 1(11.1%) Systemic Regimens 2 2 (15.4%) 2 (22.2%) 3 2 (15.4%) 1 (11.1%) 5a8 9 T 3 mg/kg T 1 mg/kg T 3 mg/kg M 20 mg/kg Q4W M 10 mg/kg Q2W M 10mg/kg Q2W Characteristic (N = 6) (N = 14) (N = 11) Age (years) 6   14  11   67.2  66.6  57.3  10.1  10.7  16.5  70.0  70.5  63.0  (50, 78) (42,77) (22, 86) Sex 3 (50.0%) 7 (50.0%) 8 (72.7%) 3 (50.0%) 7 (50.0%) 3(27.3%) Baseline ECOG Status 1 (16.7%) 8 (57.1%) 1 (9.1%) 5 (83.3%) 6(42.9%) 10 (90.9%) Histology 0 (0.0%) 3 (21.4%) 1 (9.1%) 6 (100%) 11(78.6%) 10 (90.9%) 0   0   0   Time since Initial 6   11   11  Diagnosis to Study Treatment (Months) 38.88 18.25 24.16 44.96 10.2425.64 23.10 17.40 15.10 (10.1, 128.2) (3.4, 37.7) (2.9, 82.9) MutationStatus 1 (16.7%) 3 (21.4%) 1 (9.1%) 0 (0.0%) 0 (0.0%) 1 (9.1%) 2 (33.3%)2 (14.3%) 4 (36.4%) 3 (50.0%) 6 (42.9%) 5 (45.5%) 0 (0.0%) 0 (0.0%) 0(0.0%) 0 (0.0%) 3 (21.4%) 0 (0.0%) 0   0   0   Smoking History 2 (33.3%)5 (35.7%) 3 (27.3%) 4 (66.7%) 9 (64.3%) 8 (72.7%) Number of Prior 1(16.7%) 1 (7.1%) 3 (27.3%) Systemic Regimens 0 (0.0%) 4 (28.6%) 5(45.5%) 4 (66.7%) 4 (28.6%) 0 (0.0%) TOTAL Characteristic (N = 99) Age(years) n 99   Mean 65.2  SD 9.6 Median 67.0  (Min, Max) (22, 86) SexMale 55 (55.6%) Female 44 (44.4%) Baseline ECOG Status 0 31 (31.3%) 1 68(68.7%) Histology Squamous 8 (8.3%) Non-Squamous 88 (91.7%) MISSING 3  Time since Initial n 91   Diagnosis to Study Treatment (Months) Mean24.08 SD 23.29 Median 16.80 (Min, Max) (1.0, 128.2) Mutation Status EGFR11 (11.5%) ALK 1 (1.0%) KRAS 17 (17.7%) No Mutation 56 (58.3%) Other 3(3.1%) Unknown 8 (8.3%) MISSING 3   Smoking History Never Smoked 18(18.2%) Former/Current Smoker 81 (81.8%) Number of Prior 1 22 (22.4%)Systemic Regimens 2 27 (27.6%) 3 24 (24.5%)

Various doses and schedules of MEDI4736 and tremelimumab administered incombination were examined (FIG. 15 ). MEDI4736 doses and schedulingincluded 3 mg/kg, 10 mg/kg, 15 mg/kg, and 20 mg/kg every 4 weeks (q4w)and 10 mg/kg every 2 weeks (q2w). Tremelimumab doses and schedulingincluded 1 mg/kg, 3 mg/kg, and 10 mg/kg every 4 weeks (q4w×6 doses) andevery 12 weeks (q12w×3 doses).

Complete sPD-L1 suppression at doses ≥15 mg/kg Q4W MEDI4736 was observed(FIG. 16 ). One subject each at 10 mg/kg Q4W and 15 mg/kg Q4W showedpartial sPD-L1 suppression at some visits followed by completesuppression after repeated dosing. One subject following 15 mg/kg Q4Wwas not suppressed at Day 29. By comparison, complete suppression wasobserved with single-agent MEDI4736 (Study 1108) at doses >3 mg/kg Q2W.When individual sPD-L1 profiles by cohort were examined, complete sPD-L1suppression was observed in >95% of subjects following 10 mg/kg Q2W dose(FIG. 17 ).

Increased proliferation of T cells was also observed when MEDI4736 andtremelimumab were administered in combination (FIG. 18 ). Cells weresorted by FACS analysis for the markers CD4 and CD8 in combination withKi67, a marker of cell proliferation. A monotonic increase in peakCD4+Ki67+ cells was observed with increasing tremelimumab dose, whichwas greater than the increase in peak CD4+Ki67+ observed with MEDI4736alone. The CD8+ proliferative response was greater with combinations ofMEDI4736 and tremelimumab than with MEDI4736 alone.

Increases in CD4 ICOS+ and CD4 HLADR+ cells was observed in subjectsreceiving MEDI4736 and tremelimumab compared to MEDI4736 alone (FIG. 19). Minimal changes in CD4+ICOS+ cells and CD4+HLADR+ cells was observedwith MEDI4736 alone and all tested combination doses had a patterndistinguishable from MEDI4736. Maximal increases in CD4+ICOS+ cells andCD4+HLADR+ cells were observed with a 10 mg/kg tremelimumab dose.Increase in CD4++T effector cells and Treg cells (CD25hi CD127lophenotype may also include some activated T cells) were also observed insubjects receiving MEDI4736 and tremelimumab compared to MEDI4736 alone(FIGS. 20 and 21 ).

Clinical activity in NSCLC was observed with treatment with MEDI4736 andtremelimumab (all doses) showed increases in overall response rate,compared to treatment with MEDI4736 monotherapy (10 mg/kg Q2W (FIG. 22). Response was evaluable in treated patients with measurable disease atbaseline+≥1 follow-up scan (includes discontinuations due to diseaseprogression or death prior to first follow-up scan). For MEDI4736 NSCLC(CP1108), only patients with ≥12 weeks follow-up were included. Overallresponse rate (ORR) includes confirmed and unconfirmed complete response(CR) or partial response (PR). For MEDI4736 NSCLC monotherapy (CP1108,10 mg/kg Q2W), best overall response (BOR) of stable disease (SD) withminimum duration of 12 weeks is presented. For the combination ofMEDI4736 and tremelimumab, BOR of SD with minimum duration of 7 weeks ispresented.

Decreases in or stabilization of tumor size was seen in the majority ofNSCLC patients administered MEDI4736 and tremelimumab at tremelimumabdoses of 1 mg/kg; 3 mg/kg; and 10 mg/kg (FIG. 23 ). The onset of grade 3adverse events showed that increasing the dosage of tremelimumab alsodecreased the time of onset of an adverse event (FIG. 24 ). Decreases inor stabilization of tumor size was seen in the majority of NSCLCpatients administered MEDI4736 and tremelimumab at MEDI4736 doses of 10mg/kg; 315 mg/kg; and 20 mg/kg at Q4W or 10 mg/kg at Q2W (FIG. 25 ). Theonset of grade 3 adverse events showed that increasing the dosage oftremelimumab affected the time of onset of an adverse event thanincreasing the dosage of MEDI4736 (FIG. 26 ). Thus, selection ofMEDI4736 and tremelimumab dosages will take into account efficacy andsafety.

Exposure data from single-agent tremelimumab in cancer therapy hassupported that higher exposures (>30 mg/mL) are needed to maximizeefficacy. These levels are attained, on average, at doses ≥3 mg/kg. Theexposure achieved following tremelimumab at 1 mg/kg is expected toproduce less toxicity than 3 mg/kg based on an analysis of single-agentexposure-safety relationships. Without being bound to a particulartheory, tremelimumab at 1 mg/kg partially inhibits CTLA4, asimmune-mediated adverse effects are still observed at 1 mg/kg (albeit atlower incidence). Tremelimumab at 1 mg/kg could be optimal incombination with MEDI4736 if synergistic efficacy is observed and thesafety profile is improved relative to higher tremelimumab doses.

In one study, complete suppression of the PD-L1 sink and sPD-L1 in serumwas observed at doses ≥3 mg/kg Q2W MEDI4736. A dose of 10 mg/kg Q2W waschosen for use as a single agent based on achieving >99% saturation ofthe sink in the majority of subjects, with drug levels producing maximumtumor growth inhibition (TGI) in mouse models (100 mg/mL identified asthe minimum target trough concentration). Following 10 mg/kg Q4W incombination with tremelimumab, suppression of sPD-L1 was observed insome subjects. Dose density was higher with MEDI4736 Q2W and Cmax washigher with Q4W. Scheduling with Q4W may provide greater convenience. Inother subjects, incomplete suppression was observed, possibly due toupregulation of PD-L1 combined with suboptimal trough levels achieved atthis dose level. MEDI4736 at 10 mg/kg Q4W, evaluated in combination withtremelimumab, produced trough concentrations below the target of 100mg/mL. However, target levels were achieved with MEDI4736 at 15 and 20mg/kg Q4W, and the higher doses of MEDI4736 maintained sPD-L1suppression in all subjects evaluated to date. MEDI4736 at 10 mg/kg orhigher could be optimal in combination with tremelimumab if synergisticefficacy is observed and the safety profile is improved.

Overall, the trend for the combination of MEDI4736 and tremelimumab wasto decrease or stabilize disease compared to MEDI4736 monotherapy, andMEDI4736 and tremelimumab at the highest doses tested was associatedwith increased incidence of adverse events. (FIGS. 27-29 ). Theseresults indicate that the a combination of MEDI4736 and tremelimumab iswell-tolerated and has the potential to be an effective therapy forNSCLC.

Example 4: Treatment of PD-L1 Negative Tumors in NSCLC with MED14736 andTremelimumab

Twelve subjects were treated, with 3 subjects each in Cohort 1a (1 mg/kgtremelimumab and 3 mg/kg MEDI4736), Cohort 2a (1 mg/kg tremelimumab and10 mg/kg MEDI4736), Cohort 3a (1 mg/kg tremelimumab and 15 mg/kgMEDI4736), and Cohort 3b (3 mg/kg tremelimumab and 10 mg/kg MEDI4736).Two subjects in Cohort 1a (one subject withdrew consent after 2 doses ofboth agents) completed approximately 115 days of follow-up; Cohort 2asubjects completed approximately 56 days of follow-up; and subjects inCohorts 3a and 3b completed 28 days of follow up.

Baseline levels of PD-L1 tumor expression data for 7 subjects on thestudy are provided at Table 4 (below). Additional information isprovided at Table 5.

PD-L1 Result BOR (cut-off Best Change in Cohort M Score (@25% M6-4-2014) target Lesion Cohorts (15 MEDI4736/10 Treme) 13 NEG NoAssessments NA Cohort 3a (15 MEDI4736/1 Treme) 0 NEG Unconfirmed PR65.2% Decrease Cohort 2a (10 MEDI4736/1 Treme) 0 NEG PD  3.7% IncreaseCohort 2a (10 MEDI4736/1 Treme) 7 NEG SD  1.6% Increase Cohort 3a (15MEDI4736/1 Treme) 2 NEG SD 26.7% Decrease Cohort 3b (10 MEDI4736/3Treme) 2 NEG Unconfirmed PR 38.9% Decrease Cohort 3b (10 MEDI4736/3Treme) 0 NEG PD 23.5% Increase

TABLE 5 Demographics and Baseline Characteristics PD-L1 Result 3+ Tumor2+ Tumor 1+ Tumor (@25% M Cohort SID Membrane Membrane Membrane M ScoreScore Cutoff) REC'D Cohort 5 (15 MEDI4736/10 Treme) 2000060020 0 8 5 13NEG 16 Jun. 2014 Cohort 3a (15 MEDI4736/1 Treme) 2000060009 0 0 0 0 NEG16 Jun. 2014 Cohort 2a (10 MEDI4736/1 Treme) 2000060004 0 0 0 0 NEG 16Jun. 2014 Cohort 2a (10 MEDI4736/1 Treme) 2000062007 0 5 2 7 NEG 16 Jun.2014 Cohort 3a (15 MEDI4736/1 Treme) 2000060014 0 2 0 2 NEG 16 Jun. 2014Cohort 3b (10 MEDI4736/3 Treme) 2000062015 0 1 1 2 NEG 16 Jun. 2014Cohort 3b (10 MEDI4736/3 Treme) 2000060010 0 0 0 0 NEG 16 Jun. 2014COLLECTION Best Change in Cohort DATE BOR (cut-off 6 Apr. 2014) targetLesion Current Status Cohort 5 (15 MEDI4736/10 Treme) 8 Apr. 2014 NoAssessments NA On treatment. Waiting for week 8 scans Cohort 3a (15MEDI4736/1 Treme) 8 Jan. 2014 Unconfirmed PR 65.2% Decrease Ontreatment. Waiting for week 16 scans Cohort 2a (10 MEDI4736/1 Treme) 25May 2012 PD  3.7% Increase On treatment past progression at week 20.Cohort 2a (10 MEDI4736/1 Treme) 31 Aug. 2011 SD  1.6% Increase Ontreatment at week 20. Cohort 3a (15 MEDI4736/1 Treme) 12 Jun. 2007 SD26.7% Decrease Off treatment at 8 weeks (colitis) Cohort 3b (10MEDI4736/3 Treme) 4 Oct. 2013 Unconfirmed PR 38.9% Decrease On treatmentat 12 weeks. Cohort 3b (10 MEDI4736/3 Treme) 1 Aug. 2013 PD 23.5%Increase  Off treatment at 8 weeks (colitis, PD)

Subject tissue of NSCLC patients was characterized for PD-L1 expressionby immunohistochemistry in formalin fixed and paraffin embedded tissuesamples. A sample was determined to be “PD-L1 positive” if the samplecontained 25% or more tumor cells with PD-L1 membrane staining. This isexpressed as immunohistochemistry membrane (M)-score. All samples werescored as “negative” for PD-L1 expression. Tumor assessments areavailable on 6 of 7 patients. Three patients treated with a combinationof tremelimumab and MEDI4736.

Two patients were identified as unconfirmed partial responders (PR), twohad stable disease (SD), and two had progressive disease (PD). In all 6patients, tumor samples were collected >6 months prior to analysis forPD-L1 expression, and 3 of 6 biopsy samples were collected more than 2years prior to analysis. These data indicate that a combination ofMEDI4736 and tremelimumab is active in PD-L1 negative NSCLC based onstored tissue samples.

When administered MEDI4736 and tremelimumab, most patients having PD-L1negative NSCLC responded to combination therapy, and showed decreases inor stabilization of tumor size, compared to MEDI4736 monotherapy(CP1108, 10 mg/kg Q2W) (FIG. 30 ). Patients having PD-L1 positive NSCLCalso responded to the combination of MEDI4736 and tremelimumab comparedto MEDI4736 monotherapy, and showed decreases in or stabilization oftumor size (FIG. 31 ). When the results of the patients having PD-L1negative NSCLC were grouped by the dose of tremelimumab, 1 mg/kgtremelimumab or 3 mg/kg tremelimumab administered in combination withMEDI4736 at 10 mg/kg Q4W or 15 mg/kg Q4W were effective at controllingor reducing disease (FIG. 32 ). When the results were grouped by thedose of MEDI4736, the results also showed that tremelimumab at 1 mg/kgto 3 mg/kg administered in combination with MEDI4736 at 10 mg/kg Q4W to15 mg/kg Q4W was effective at controlling or reducing disease (FIG. 33). Analysis of all NSCLC patients receiving MEDI4736 and tremelimumabshowed that PD-L1− and PD-L1+ NSCLC patients responded to treatment(FIGS. 34A-34D and 35-37 ; Tables 6-9).

TABLE 6 Best Overall Response - All Evaluable Subjects ResponseEvaluable Population MEDI4736 (M) and Tremelimumab (T) Cohort 1a 2a 3a3b 3 mg/kg (M) + 10 mg/kg (M) + 15 mg/kg (M) + 10 mg/kg (M) + 1 mg/kg(T) 1 mg/kg (T) 1 mg/kg (T) 3 mg/kg (T) Q4W Q4W Q4W Q4W N = 3 N = 3 N =12 N = 3 Complete Response 0 (0.0%) 0 (0.0%)  0 (0.0%)  0 (0.0%) Partial Response 0 (0.0%) 1 (33.3%) 4 (33.3%) 1 (33.3%) Stable Disease 0(0.0%) 1 (33.3%) 4 (33.3%) 1 (33.3%) Progressive Disease  3 (100%) 1(33.3%) 1 (8.3%)  1 (33.3%) Not Evaluable 0 (0.0%) 0 (0.0%)  3 (25.0%) 0(0.0%)  MEDI4736 (M) and Tremelimumab (T) Cohort 4 4a 5 20 mg/kg (M) +15 mg/kg (M) + 15 mg/kg (M) + 1 mg/kg (T) 3 mg/kg (T) 10 mg/kg (T) Q4WQ4W Q4W N = 11 N = 13 N = 9 Complete Response 0 (0.0%)  0 (0.0%)  0(0.0%)  Partial Response 3 (27.3%) 4 (30.8%) 2 (22.2%) Stable Disease 2(18.2%) 3 (23.1%) 1 (11.1%) Progressive Disease 4 (36.4%) 4 (30.8%) 6(66.7%) Not Evaluable 2 (18.2%) 2 (15.4%) 0 (0.0%)  MEDI4736 (M) andTremelimumab (T) Cohort 5a 8 9 20 mg/kg (M) + 10 mg/kg (M) + 10 mg/kg(M) + 3 mg/kg (T) 1 mg/kg (T) 3 mg/kg (T) Q4W Q2W Q2W All Cohorts N = 6N = 10 N = 9 N = 79 Complete Response 0 (0.0%)  0 (0.0%)  0 (0.0%)  0(0.0%) Partial Response 1 (16.7%) 0 (0.0%)  2 (22.2%) 18 (22.8%) StableDisease 2 (33.3%) 3 (30.0%) 2 (22.2%) 19 (24.1%) Progressive Disease 1(16.7%) 5 (50.0%) 4 (44.4%) 30 (38.0%) Not Evaluable 2 (33.3%) 2 (20.0%)1 (11.1%) 12 (15.2%)

TABLE 7 Best Overall Response - PD-L1 Positive Subjects ResponseEvaluable Population MEDI4736 (M) and Tremelimumab (T) Cohort 1a 2a 3a3b 3 mg/kg (M) + 10 mg/kg (M) + 15 mg/kg (M) + 10 mg/kg (M) + 1 mg/kg(T) 1 mg/kg (T) 1 mg/kg (T) 3 mg/kg (T) Q4W Q4W Q4W Q4W N = 0 N = 0 N =2 N = 0 Complete Response 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) PartialResponse 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Stable Disease 0 (0.0%) 0(0.0%)  1 (50.0%) 0 (0.0%) Progressive Disease 0 (0.0%) 0 (0.0%) 0(0.0%) 0 (0.0%) Not Evaluable 0 (0.0%) 0 (0.0%)  1 (50.0%) 0 (0.0%)MEDI4736 (M) and Tremelimumab (T) Cohort 4 4a 5 20 mg/kg (M) + 15 mg/kg(M) + 15 mg/kg (M) + 1 mg/kg (T) 3 mg/kg (T) 10 mg/kg (T) Q4W Q4W Q4W N= 4 N = 0 N = 3 Complete Response 0 (0.0%) 0 (0.0%) 0 (0.0%)  PartialResponse  3 (75.0%) 0 (0.0%) 1 (33.3%) Stable Disease  1 (25.0%) 0(0.0%) 1 (33.3%) Progressive Disease 0 (0.0%) 0 (0.0%) 1 (33.3%) NotEvaluable 0 (0.0%) 0 (0.0%) 0 (0.0%)  MEDI4736 (M) and Tremelimumab (T)Cohort 5a 8 9 20 mg/kg (M) + 10 mg/kg (M) + 10 mg/kg (M) + 3 mg/kg (T) 1mg/kg (T) 3 mg/kg (T) Q4W Q2W Q2W All Cohorts N = 2 N = 1 N = 4 N = 16Complete Response 0 (0.0%) 0 (0.0%) 0 (0.0%)  0 (0.0%)  Partial Response0 (0.0%) 0 (0.0%) 2 (50.0%) 6 (37.5%) Stable Disease  1 (50.0%) 0 (0.0%)1 (25.0%) 5 (31.3%) Progressive Disease 0 (0.0%)  1 (100%) 0 (0.0%)  2(12.5%) Not Evaluable  1 (50.0%) 0 (0.0%) 1 (25.0%) 3 (18.8%)

TABLE 8 Best Overall Response - PD-L1 Negative Subjects ResponseEvaluable Population MEDI4736 (M) and Tremelimumab (T) Cohort 1a 2a 3a3b 3 mg/kg (M) + 10 mg/kg (M) + 15 mg/kg (M) + 10 mg/kg (M) + 1 mg/kg(T) 1 mg/kg (T) 1 mg/kg (T) 3 mg/kg (T) Q4W Q4W Q4W Q4W N = 2 N = 3 N =6 N = 3 Complete Response 0 (0.0%) 0 (0.0%)  0 (0.0%)  0 (0.0%)  PartialResponse 0 (0.0%) 1 (33.3%) 3 (50.0%) 1 (33.3%) Stable Disease 0 (0.0%)1 (33.3%) 1 (16.7%) 1 (33.3%) Progressive Disease  2 (100%) 1 (33.3%) 1(16.7%) 1 (33.3%) Not Evaluable 0 (0.0%) 0 (0.0%)  1 (16.7%) 0 (0.0%) MEDI4736 (M) and Tremelimumab (T) Cohort 4 4a 5 20 mg/kg (M) + 15 mg/kg(M) + 15 mg/kg (M) + 1 mg/kg (T) 3 mg/kg (T) 10 mg/kg (T) Q4W Q4W Q4W N= 5 N = 6 N = 3 Complete Response 0 (0.0%)  0 (0.0%)  0 (0.0%) PartialResponse 0 (0.0%)  3 (50.0%)  1 (33.3%) Stable Disease 1 (20.0%) 1(16.7%) 0 (0.0%) Progressive Disease 3 (60.0%) 1 (16.7%)  2 (66.7%) NotEvaluable 1 (20.0%) 1 (16.7%) 0 (0.0%) MEDI4736 (M) and Tremelimumab (T)Cohort 5a 8 9 20 mg/kg (M) + 10 mg/kg (M) + 10 mg/kg (M) + 3 mg/kg (T) 1mg/kg (T) 3 mg/kg (T) Q4W Q2W Q2W All Cohorts N = 2 N = 4 N = 1 N = 35Complete Response 0 (0.0%) 0 (0.0%)  0 (0.0%) 0 (0.0%)  Partial Response0 (0.0%) 0 (0.0%)  0 (0.0%) 9 (25.7%) Stable Disease  1 (50.0%) 2(50.0%)  1 (100%) 9 (25.7%) Progressive Disease  1 (50.0%) 1 (25.0%) 0(0.0%) 13 (37.1%)  Not Evaluable 0 (0.0%) 1 (25.0%) 0 (0.0%) 4 (11.4%)

TABLE 9 Best Overall Response - PD-L1 NA Subjects Response EvaluablePopulation MEDI4736 (M) and Tremelimumab (T) Cohort 1a 2a 3a 3b 3 mg/kg(M) + 10 mg/kg (M) + 15 mg/kg (M) + 10 mg/kg (M) + 1 mg/kg (T) 1 mg/kg(T) 1 mg/kg (T) 3 mg/kg (T) Q4W Q4W Q4W Q4W N = 1 N = 0 N = 4 N = 0Complete Response 0 (0.0%) 0 (0.0%) 0 (0.0%)  0 (0.0%) Partial Response0 (0.0%) 0 (0.0%) 1 (25.0%) 0 (0.0%) Stable Disease 0 (0.0%) 0 (0.0%) 2(50.0%) 0 (0.0%) Progressive Disease  1 (100%) 0 (0.0%) 0 (0.0%)  0(0.0%) Not Evaluable 0 (0.0%) 0 (0.0%) 1 (25.0%) 0 (0.0%) MEDI4736 (M)and Tremelimumab (T) Cohort 4 4a 5 20 mg/kg (M) + 15 mg/kg (M) + 15mg/kg (M) + 1 mg/kg (T) 3 mg/kg (T) 10 mg/kg (T) Q4W Q4W Q4W N = 2 N = 7N = 3 Complete Response 0 (0.0%) 0 (0.0%)  0 (0.0%) Partial Response 0(0.0%) 1 (14.3%) 0 (0.0%) Stable Disease 0 (0.0%) 2 (28.6%) 0 (0.0%)Progressive Disease  1 (50.0%) 3 (42.9%)  3 (100%) Not Evaluable  1(50.0%) 1 (14.3%) 0 (0.0%) MEDI4736 (M) and Tremelimumab (T) Cohort 5a 89 20 mg/kg (M) + 10 mg/kg (M) + 10 mg/kg (M) + 3 mg/kg (T) 1 mg/kg (T) 3mg/kg (T) Q4W Q2W Q2W All Cohorts N = 2 N = 5 N = 4 N = 28 CompleteResponse 0 (0.0%) 0 (0.0%)  0 (0.0%) 0 (0.0%)  Partial Response  1(50.0%) 0 (0.0%)  0 (0.0%) 3 (10.7%) Stable Disease 0 (0.0%) 1 (20.0%) 0(0.0%) 5 (17.9%) Progressive Disease 0 (0.0%) 3 (60.0%)  4 (100%) 15(53.6%)  Not Evaluable  1 (50.0%) 1 (20.0%) 0 (0.0%) 5 (17.9%)

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificaspects of the disclosure described herein. Such equivalents areintended to be encompassed by the following claims.

Various publications are cited herein, the disclosures of which areincorporated by reference in their entireties.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be obvious that certain changes and modificationscan be practiced within the scope of the appended claims.

SEQUENCE LISTING SEQ ID NO: 1 MEDI4736 VLEIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWT FGQGTKVEIKSEQ ID NO: 2 MEDI4736 VHEVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSS SEQ ID NO: 3-MEDI4736 VH CDR1 RYWMSSEQ ID NO: 4-MEDI4736 VH CDR2 NIKQDGSEKYYVDSVKGSEQ ID NO: 5-MEDI4736 VH CDR3 EGGWFGELAFDY SEQ ID NO: 6-MEDI4736 VL CDR1RASQRVSSSYLA SEQ ID NO: 7-MEDI4736 VL CDR2 DASSRATSEQ ID NO: 8-MEDI4736 VL CDR3 QQYGSLPWT SEQ ID NO: 9 Tremelimumab VLPSSLSASVGDRVTITCRASQSINSYLDWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPFTFGPGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV SEQ ID NO: 10 Tremelimumab VHGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDPRGATLYYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKD YFPEPVTVSWNSGALTSGVHSEQ ID NO: 11-Tremelimumab VH CDR1 GFTFSSYGMHSEQ ID NO: 12-Tremelimumab VH CDR2 VIWYDGSNKYYADSVSEQ ID NO: 13-Tremelimumab VH CDR3 TAVYYCARDPRGATLYYYYYGMDVSEQ ID NO:14-Tremelimumab VL CDR1 RASQSINSYLDSEQ ID NO: 15-Tremelimumab VL CDR2 AASSLQSSEQ ID NO: 16-Tremelimumab VL CDR3 QQYYSTPFT

1-27. (canceled)
 28. A method of treating non-small cell lung carcinoma(NSCLC) in a human patient comprising administering MEDI4736 or anantigen-binding fragment thereof and tremelimumab or an antigen-bindingfragment thereof to the patient, wherein the administrations increaseprogression-free survival.
 29. The method of claim 28, wherein theadministrations result in an increase in progression-free survival ascompared to the administration of either the MEDI4736 or anantigen-binding fragment thereof or the tremelimumab or anantigen-binding fragment thereof alone. 30-31. (canceled)
 32. The methodof claim 28, wherein the administrations result in a tumor response. 33.The method of claim 32, wherein the administrations result in anincreased tumor response as compared to the administration of either theMEDI4736 or an antigen-binding fragment thereof or the tremelimumab oran antigen-binding fragment thereof alone.
 34. The method of claim 32,wherein the tumor response can be detected by week 8 or week
 33. 35-37.(canceled)
 38. The method of claim 28, wherein the administrationsincrease overall survival.
 39. The method of claim 38, wherein theadministrations result in an increase in overall survival as compared tothe administration of either the MEDI4736 or an antigen-binding fragmentthereof or the tremelimumab or an antigen-binding fragment thereof alone40. (canceled)
 42. The method of claim 28, wherein the administration oftremelimumab or an antigen-binding fragment thereof is repeated aboutevery 12 weeks.
 43. The method of claim 28, wherein the administrationof tremelimumab or an antigen-binding fragment thereof is administeredabout every 4 weeks for seven administrations and then every 12 weeks.44. The method of claim 28, wherein the administration reduces solublePD-L1.
 45. The method of claim 44, wherein soluble PD-L1 is reduced byat least 65%, 80%, 90%, 95%, or 99%. 46-49. (canceled)
 50. The method ofclaim 28, wherein the NSCLC is refractory to at least onechemotherapeutic agent.
 51. The method of claim 50, wherein thechemotherapeutic agent is Vemurafenib, Erlotinib, Afatinib, Cetuximab,Carboplatin, Bevacizumab, Erlotinib, Gefitinib, or Pemetrexed.
 52. Themethod of claim 28, wherein the patient has an Eastern CooperativeOncology Group (ECOG) performance status of 0-1.
 53. The method of claim28, wherein the patient is immunotherapy-naïve prior to theadministration of MEDI4736 or antigen-binding fragment thereof andtremelimumab or antigen-binding fragment thereof.
 54. The method ofclaim 28, wherein the patient has received immunotherapy prior to theadministration of MEDI4736 or antigen-binding fragment thereof andtremelimumab or antigen-binding fragment thereof.
 55. The method ofclaim 28, wherein the administration of MEDI4736 or an antigen-bindingfragment thereof is by intravenous infusion and/or the administration oftremelimumab or an antigen-binding fragment thereof is by intravenousinfusion.
 56. (canceled)
 57. The method of claim 28, wherein theMEDI4736 or an antigen-binding fragment thereof is MEDI4736 and whereinthe tremelimumab or an antigen-binding fragment thereof is tremelimumab.58. The method of claim 28, wherein the administrations reduce tumorsize by at least about 10%, 25%, or 50% relative to baseline. 59.(canceled)
 60. The method of claim 28, wherein the human patient haslocally advanced unresectable or metastatic NSCLC.
 61. The method ofclaim 28, wherein the NSCLC is squamous or non-squamous.
 62. The methodof claim 28, wherein the NSCLC comprises a KRAS-mutation or anEGFR-mutation.
 63. The method of claim 28, wherein the NSCLC is PD-L1positive or PD-L1 negative.
 64. (canceled)
 65. A method of treatmentcomprising administering MEDI4736 or an antigen-binding fragment thereofand tremelimumab or an antigen-binding fragment thereof to a patientidentified as having a PD-L1− or PD-L1+ NSCLC. 66-101. (canceled)